prld-10k_20211231.htm

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2021

Commission File Number 001-39527

PRELUDE THERAPEUTICS INCORPORATED

(Exact name of Registrant as specified in its Charter)

200 Powder Mill Road Wilmington, Delaware 19803

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (302) 467-1280

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, par value $0.0001 per share PRLD The Nasdaq Stock Market LLC

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes☐No☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes☐No☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes☒No☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes☒No☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes☐No☒

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant was approximately $343.3 million as of the last business day of the registrant’s most recently completed second fiscal quarter, based upon the closing sale price on The Nasdaq Stock Market LLC reported for such date. This excludes an aggregate of 35,047,353 shares of the registrant’s common stock held as of such date by officers, directors and stockholders that the registrant has concluded are or were affiliates of the registrant. Exclusion of such shares should not be construed to indicate that the holder of any such shares possesses the power, direct or indirect, to direct or cause the direction of the management or policies of the registrant or that such person is controlled by or under common control with the registrant.

The number of shares of Registrant’s Common Stock outstanding as of March 11, 2022 was 47,631,741.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s Definitive Proxy Statement (“Proxy Statement”) relating to the 2022 Annual Meeting of Stockholders will be filed with the Commission within 120 days after the end of the Registrant’s 2021 fiscal year pursuant to Regulation 14A and is incorporated by reference into Part III of this Report. Except with respect to information specifically incorporated by reference in this Form 10-K, the Proxy Statement is not deemed to be filed as part of this Form 10-K.

Table of Contents

Page

PART I

Item 1. Business 2

Item 1A. Risk Factors 33

Item 1B. Unresolved Staff Comments 84

Item 2. Properties 84

Item 3. Legal Proceedings 84

Item 4. Mine Safety Disclosures 84

PART II

Item 6. [Reserved] 85

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 95

Item 8. Financial Statements and Supplementary Data 95

Item 9A. Controls and Procedures 117

Item 9B. Other Information 117

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 117

PART III

Item 10. Directors, Executive Officers and Corporate Governance 118

Item 11. Executive Compensation 118

Item 14. Principal Accounting Fees and Services 118

PART IV

Item 15. Exhibits and Financial Statement Schedules 119

PART I

This Annual Report on Form 10-K contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements are based on our management’s beliefs and assumptions and on information currently available to our management. All statements other than statements of historical facts are “forward-looking statements” for purposes of these provisions, including those relating to future events or our future financial performance. In some cases, you can identify forward-looking statements by terminology such as “may,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “project,” “believe,” “estimate,” “predict,” “potential,” “intend” or “continue,” the negative of terms like these or other comparable terminology, and other words or terms of similar meaning. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. All forward-looking statements included in this Annual Report on Form 10-K are based on information available to us on the date hereof, and we assume no obligation to update any such forward-looking statements. Our forward-looking statements can be affected by inaccurate assumptions we might make or by known or unknown risks, uncertainties and other factors. We discuss many of these risks, uncertainties and other factors in this Annual Report on Form 10-K in greater detail under the heading “Item 1A—Risk Factors.” It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this Annual Report on 10-K may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements.

Item 1. Business.

Overview

We are a clinical-stage fully integrated oncology company built on a foundation of drug discovery excellence to deliver novel precision cancer medicines to underserved patients. By leveraging our core competencies in cancer biology and medicinal chemistry, combined with our target class- and technology platform-agnostic approach, we have built an efficient, fully-integrated drug discovery engine to identify compelling biological targets and create new chemical entities, or NCEs, that we rapidly advance into clinical trials. We believe our approach could result in better targeted cancer therapies. Our discovery excellence has been validated by our rapid progress in creating a wholly-owned, internally developed pipeline. Since our inception in 2016, we have received clearance from the U.S. Food and Drug Administration, or the FDA, for six investigational new drug applications, or INDs, and successfully advanced these programs into clinical trials. In addition, we have two unique programs in various stages of preclinical development that we plan to advance into clinical development in 2022.

By focusing on developing agents using broad mechanisms that have multiple links to oncogenic driver pathways in select patients, we have developed a diverse pipeline consisting of six distinct programs spanning methyltransferases, kinases, protein-protein interactions and targeted protein degraders. Our pipeline is geared towards serving patients with high unmet medical need where there are limited or no treatment options. We believe we can best address these diseases by developing therapies that target primary and secondary resistance mechanisms.

The following table summarizes our product candidate pipeline:

Our most advanced candidates are designed to be oral, potent and selective inhibitors of protein arginine methyltransferase 5, or PRMT5. The potency and selectivity of our product candidates is supported by preclinical data demonstrating nanomolar inhibition of PRMT5 and no inhibition of related enzymes at 1,000 times higher concentration of our product candidates. PRT543, our first clinical candidate, is currently in a Phase 1 clinical trial in advanced solid tumors and select myeloid malignancies. As of an August 6, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT543 enrolled a total of 49 patients across 18 unselected advanced solid tumors and lymphoma. Patients enrolled in the trial received an average of three prior lines of therapy. PRT543 demonstrated target engagement and inhibition of PRMT5 functional activity as evidenced by a 69% reduction in serum symmetric dimethylarginine, or sDMA, at a dose of 45 mg/5x per week. In addition, PRT543 demonstrated signs of preliminary clinical activity, including a durable complete response, or CR, maintained for over 18 months in a patient with HRD+ ovarian cancer who remains on treatment, and prolonged stable disease, or SD, persisting for over six months in five patients, including four patients with ACC and one patient with uveal melanoma. A complete response is defined as the disappearance of all target lesions. PRT543 was generally well tolerated: the most common grade 3 or higher treatment-related adverse events, or AEs, occurring in at least 5% of patients were thrombocytopenia (27%) and anemia (12%), both of which were reversible upon treatment interruption. Patients were largely able to remain on therapy with few AE-related dose interruptions (27%), reductions (22%), or discontinuations (4%).

Patient enrollment is continuing in specific biomarker-selected solid tumor and hematologic malignancy expansion cohorts. We anticipate presenting data from those expansion cohorts in the second half of 2022.

PRT811, our second clinical candidate, is a PRMT5 inhibitor that we have optimized for high brain exposure. PRT811 is being studied in a Phase 1 clinical trial in unselected patients with solid tumors, including high-grade glioma. As of an August 13, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT811 enrolled a total of 45 patients, including 27 patients across 16 unselected advanced solid tumors and 18 patients with high-grade gliomas, including 17 patients with glioblastoma multiforme. PRT811 demonstrated dose dependent inhibition of PRMT5 activity as evidenced by an 83% reduction in serum sDMA at a dose of 600 mg daily (QD). In addition, PRT811 demonstrated signs of preliminary clinical activity, including an IDH1 mutated high-grade glioma (glioblastoma (GBM)) patient who experienced a partial response, or PR, that evolved into a durable CR for more than 13 months. In addition, a patient with splicing-mutant, or SF3B1, uveal melanoma demonstrated SD for more than six months with a 25% tumor regression. At a post data-cutoff on September 20, 2021, one additional patient (receiving a dose of 800 mg QD) with SF3B1 uveal melanoma had an unconfirmed PR and 47% decrease in target lesion, and a patient with triple negative breast cancer (receiving a dose of 800 mg QD) demonstrated a 27% decrease in target lesions. PRT811 was generally well-tolerated; the most common grade 3 or higher treatment-related AE was thrombocytopenia (7%), which was reversible upon treatment interruption. Patients were largely able to remain on therapy with few AE-related dose interruptions (13%), reductions (4%), or discontinuations (3%).

On March 9, 2022, we announced that we are concentrating our further development efforts on PRT811 in biomarker-selected patients in specific cancer types. While the Company believes that both PRT811 and PRT543 are high quality,

clinically active compounds, PRT811 was selected based on its superior safety profile, higher level of target engagement, and unique brain penetrant properties.

Specifically, we intend to:

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. The potency and selectivity of PRT1419 is supported by preclinical data demonstrating nanomolar inhibition of MCL1 and no inhibition of related enzymes at 200 times higher concentration of our product candidate. We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into the Phase 1 clinical trial for the oral formulation of PRT1419. The dose escalation portion of the Phase 1 trial of both oral formulation and the intravenous, IV, formulation, which leverages the optimized physicochemical properties of PRT1419, are underway in patients with solid tumors and hematologic malignancies.

On March 9, 2022, we announced that we are prioritizing development of the IV formulation of PRT1419, which demonstrated a desirable pharmacokinetic, pharmacodynamic and safety profile with potential for differentiation from competitor compounds. We intend to initiate a combination trial with venetoclax by mid-year with the goal of establishing safety, clinical activity and a recommended Phase 2 dose in the second half of 2022.

PRT2527, our fourth clinical candidate, is designed to be a potent and selective Cyclin-dependent kinase 9, or CDK9, inhibitor. In preclinical studies, PRT2527 was shown to reduce MCL1 and MYC protein levels and was highly active in preclinical models at well-tolerated doses. PRT2527 has demonstrated high potency and kinase selectivity which may offer improved efficacy and safety compared to less selective CDK9 inhibitors. Preclinical data demonstrated that treatment with PRT2527 depleted oncogenic drivers with short half-lives, such as MYC and MCL1, and effectively induced apoptosis. PRT2527 treatment demonstrated robust efficacy in both hematological malignancies and solid tumor models with MYC dysregulation. A phase one trial is underway evaluating escalating IV doses of PRT2527 as a monotherapy in patients with selected solid tumors, including sarcoma, prostate cancer, lung cancer, and other cancers with genomic alterations that lead to MYC dependence.

On March 9, 2022, we announced that we intend to complete enrollment in the Phase 1 dose escalation study of PRT2527 with the goal of identifying a recommended Phase 2 dose in the second half of 2022.

In addition to our four clinical stage candidates, we are advancing two new preclinical programs. Our most advanced preclinical program has led to the identification of PRT3645, a brain penetrant molecule that potently and selectively targets CDK4/6. IND-enabling studies for PRT3645 are ongoing and we plan to complete IND-enabling studies, file an IND and initiate a Phase 1 clinical trial in the second half of 2022. Our second pre-clinical program targets Brahma homologue, or BRM, otherwise known as SMARCA2. We have identified SMARCA2 protein degraders that demonstrate selective degradation of SMARCA2 at sub-nanomolar concentrations. We are currently profiling our lead compound, PRT-SCA2, and plan to submit an IND application by year-end 2022.

Prelude Discoveryand DevelopmentApproach

Wecarefullyevaluateandselectourtargetsbasedonthreekeypillars,whichprovideaframeworkfor optimizingour drug discoveryand developmentefforts.

• Identify target mechanisms with compelling biological rationale

• Pursue targets that drive cancers with high unmet need

Once we have identified optimal targets using the three pillars above, we engage our unique discovery engine to rapidly and efficiently invent and develop molecules. We believe our expertise, capabilities and experience to select high value biological targets and invent molecules with an optimized balance of biological and chemical properties differentiates us from others in the precision oncology space. We believe our unique discovery engine will enable us to continue delivering a new IND every 12 to 18 months.

We design our clinical trials to leverage the broad utility of our compounds with a focus on efficient regulatory pathways to enable our potentially transformative medicines to quickly reach patients with high unmet medical need. By focusing on validated cancer signaling pathways and early clinical proof-of-concept, we seek to advance our programs through expedited approval processes.

Our Strategy

We aimto createbettertargetedand moreeffectivecancertherapies.Our goalisto transformthe lives of patientswithcancerbyleveragingthecorecompetenciesof our experiencedteamin medicinalchemistry,cancer biologyandclinicaldevelopmentto bringnoveldrugsto market.We intendto becomea fullyintegratedoncologycompany on the foundation of drug discovery excellence to deliver novel precision oncology medicines to patients with underserved cancers by pursuingthefollowingobjectives:

Cancer Background and Treatment

Canceristhesecond-leadingcauseofdeathintheUnitedStates.TheAmericanCancerSocietyestimates thatapproximately1.9millionnewcancercaseswillbediagnosedandmorethan608,570 peopleareexpectedto dieofthediseaseintheUnitedStatesin2021.CancerisadiseaseofthegenomecausedbychangesinDNA that altercellbehavior,growthanddivision.Thesechangescancausecellstoproduceabnormalamountsof certain proteinsand/orto makeaberrantproteinsthatdo not functionproperly.It is widely understood that cancer cells caneventuallyevadetherapiesthroughmutationsor otherresistancemechanisms,limitingthelong-termsuccess of drug therapies.

Historically,cancerhasbeentreatedwithsurgery,radiationanddrugtherapywith patientsoftenreceivinga combinationofthesetreatmentmodalities.Whilesurgeryandradiationcan be effectivein patientswith localized disease,drugtherapiesareoftenrequiredwhenthecancerhasspreadbeyondtheprimarysiteorisnotamenable to resection.

Drugtherapyisintendedtokillor damagemalignantcellsby interferingwith thebiologicalprocessesthat controldevelopment,growthandsurvivalofcancercells.Thistreatmentmodalityhasevolvedovertimefrom theuse of non-specificcytotoxictherapiesto precisiononcologymedicinestargetingmolecularpathwaysor oncogenicdrivers.These precisionmedicinesarebroadlyknown as targetedtherapies.

Our Product Candidates

PRMT5Inhibitors:PRT543& PRT811

RationalefortargetingthePRMT5 pathway in cancer

Cancerisadiseaseofthegenomeandallcancershavegenomiclesionsthatmustbe addressedto develop effectivetreatments.Thesegenomicchangesareimportantatallstagesof cancerprogression,includinginitial formation,growth,andmetastasis,andresultin theupregulationof genesthatpromotecellgrowth and survival togetherwith thedownregulationof genesthatsuppresstumorgrowth.

PRMT5 controlsanumberofthebiologicalprocessesthatdrivecancerincludingtranscription,translation, DNArepairandcellsignaling.OverexpressionandincreasedenzymaticactivityofPRMT5 areassociatedwith poor outcomeand decreasedsurvivalin multiplehumancancersettings,as outlinedin thetablebelow.

This information is based on published data in peer-reviewed journals and reflects standard therapeutic intervention.

PRMT5 RegulatesTranscriptionand Translationof Cancer-relatedGenes

TheoncogenicprocesscontrolledbyPRMT5 ismediatedthroughthesymmetricdimethylationofarginines onitssubstrateproteins(Figure1).PRMT5, anintracellularenzyme,transferstwo methylgroupsfroma co- factorS-adenosylmethionine,orSAM,anddepositsthemonitssubstrateproteinsresultingin theformationof a symmetricdimethylarginine,or sDMA, mark.This post-translationalmodificationaltersthe protein structure, impactsinteractionswithDNA, andalsogeneratesdockingsitesforeffectormoleculesthatcan promotetumor cellgrowth and survival.PRMT5substrateproteinsinclude:

RNA; and

RNA.

Figure 1. PRMT5 Pathway Drives Oncogenesis and Resistance

Throughargininemethylationofhistones,transcription factorsandthespliceosomecomplex,PRMT5regulatestheexpressionofgenes involvedinpromotingcancercellgrowthandsurvival.Theseincludecellcyclegenes,tumorsuppressors, oncogenes,andgenesinvolvedin proliferationand signaling.

PRMT5-regulatedtranscriptionfactors,includingcyclinD1andMYC, haveawell-establishedroleina numberofcancers.Conversely,PRMT5-mediatedmethylationof histonessuch as H3 and H4 repressesa number oftumorsuppressorgenesincludingretinoblastoma,orRB,familymembers,contributingto unchecked proliferationofmalignantcells.Inaddition,PRMT5 symmetricallydimethylatesribosomalbindingproteinsand modulates mRNA translation of internal ribosome entry site-containing mRNAs, further promoting the generationofoncogenicproteins.Consistentwithitsroleinpromotingcancer,PRMT5inhibitionhasbeen showntodecreasetumorgrowthinpreclinicalmodels.Therefore,PRMT5 isbelievedtoserveasanimportant mediatorofcancerprogressionand can be targetedto treata rangeof solidtumorsand hematological malignancies.These attributesmakePRMT5an idealtherapeutictargetforcancer.

TheroleofPRMT5 inregulatinggenetranscriptionandtranslationmaybeparticularlyrelevantin cancers suchasACC whereupto86%ofpatientsharborthegenefusionoftheMYBfamilymembersMYB or MYBL1 withtheNuclearFactor1B,or NFIB, gene. MYB or MYBL1 gene fusionsleadto overexpressionof theMYB/ MYBL1 protein.PublisheddatademonstratethatMYBoverexpressionisimportantfordrivingcellproliferation andtumorgrowthinpreclinicalACCmodels.Inaddition,ourinternaldataillustratethatPRMT5 inhibition decreasedMYBexpressionlevelsinMYB-dependentpreclinicalmodelsandinhibitedtumorgrowthin PDX modelsofACC. RecentevidenceofclinicalactivitywithathirdpartyPRMT5 inhibitorin patientswith ACC furthervalidatesPRMT5as a potentialtargetmechanismin thishighlyunderservedcancer.

PRMT5 RegulatesmRNASplicingin Cancer Cells

Inadditiontoregulatingtranscription,PRMT5 alsomodulatesgeneexpressionbycontrollingmRNA splicing.Splicingisafundamentalcellularprocessthatinvolvestheremovalof noncodingsequencesfromthe precursormRNAtoproducethematureformthatencodesforprotein.IntheabsenceofcorrectmRNA splicing, mutatedor unstableproteinsareproduced,ultimatelyleadingto cellcycledefects,senescenceand apoptosis.The splicingreactioniscarriedoutbyamulti-protein/RNAcomplexcalledthespliceosome.PRMT5 playsan importantroleinthesplicingofmRNA throughmethylationofspliceosomeprotein,whichiscriticalforthe assemblyofthespliceosomecomplexanditsfunction.Inpreclinicalmodels,tumorswithhigh degreesof proliferation,suchasMYC-driventumors,wereassociatedwithincreasedactivityofPRMT5 tomaintainthe fidelityof thespliceosome,demonstratingtheimportanceof PRMT5in thisprocess.

TheroleofPRMT5 inregulatingmRNA splicingmaybemostrelevantin cancerswith spliceosomal mutationsorthosethataredependentonhighsplicingfidelity,suchasGBM. Spliceosomalmutationsalsooccur inmorethan50% of MDS patientsand atlowerfrequenciesin othertumortypesincludingMF, chronic myelomonocyticleukemia,AML,NHL,MM,chroniclymphocyticleukemia,orCLL,anduvealmelanoma. These spliceosomalalterationsareoftencorrelated

with highermutationalburdenand/orpoor prognosis. In modelsofAML,preclinicaldatademonstratedthatPRMT5 inhibitionresultedinhigherlevelsofsuppressionof thegrowthofcancercellscontainingmutatedspliceosomeproteinscomparedto thosecontainingunmutated spliceosomeproteins.

Syntheticlethalityfrom PRMT5 inhibitionin certainsettings

Syntheticlethalityappliesto specificpairsof genes.A syntheticlethalinteractionoccurswhen a deficiency ineithergenealoneisviablewhereasadeficiencyinbothgenessimultaneouslyresultsincelldeath.In cancer, syntheticlethalitycanbeexploitedtoselectivelykillcancercellsinwhichonegeneinthepairismutatedor deletedinthetumorcellandtheremainingsecondgene istherapeuticallyinhibited.This leadsto deathof the cancercellswhereasnormalcells,whichlackthespecificgeneticalteration,aresparedtheeffectofthedrug. In thecaseofPRMT5, ithasbeendemonstratedthatcertaingenomicalterationsconferaselectivedependenceon PRMT5 sothatPRMT5 inhibitioncanbe utilizedto producea syntheticlethaleffect.For example,PRMT5 inhibitionshows a modestpreferentialimpairmentof cellviabilityin methylthioadenosinephosphorylase,or MTAP,-nullcancercellscomparedtonormalcells,suggestingthatPRMT5 inhibitorscouldproduceasynthetic lethaleffectin GBM,in which nearlyhalfof thepatientscarrytheMTAP deletion.

ThesyntheticlethaleffectofpharmacologicalinhibitorsofDNA repairmechanismssuchaspolyADP- ribosepolymerases,orPARPs,havebeensuccessfullyutilizedinthetreatmentofHRD+cancers.HRD+can occuras a resultof geneticor epigeneticmechanismsthatresultin lossof genessuch as breastcancer genes, or BRCA1 andBRCA2,thatarerequiredforefficientDNA repair.Morerecentdatasupportthepotentialsynthetic lethalityofPRMT5inhibitionintumorsthatareHRD+duetotheroleofPRMT5inDNArepair(Figure2). PRMT5upregulates the transcription of genes involved in HRrepair to regulate the DNAdamage repair response.PRMT5 inhibitionhasbeenshownpreclinicallyto decreaseexpressionof thesegenesto inducecell death,supportingthepotentialof PRMT5inhibitorsin HRD+tumors.

Together,thesedatasupportthedevelopmentofPRMT5 inhibitorsinselectsolidtumorsandhematologic malignancies.

PRT543

Overview

WearecurrentlyadvancingourfirstclinicalcandidatePRT543,anoralinhibitorofPRMT5 inaPhase1 clinicaltrialin advancedsolidtumorsand selectmyeloidmalignancies.

Clinical Trial Design and Schema

Our PRT543 Phase 1 clinical trial design seeks to leverage PRT543’s broad potential therapeutic utility to rapidly generate proof-of-concept across multiple solid tumors and myeloid malignancies. Trial enrollment of patients with relapsed/refractory, or R/R, advanced solid tumors, NHL (Group A) or R/R MF or MDS (Group B) commenced in February 2019 and is being conducted at approximately 25 sites throughout the United States. This clinical trial consists of two parts, a dose escalation portion followed by dose expansion into separate tumor-specific cohorts. Enrollment into the additional dose expansion cohorts began early in the second quarter of 2021. Total expected enrollment is anticipated to be approximately 165 patients.

Phase 1 Clinical Trial of PRT543

All data are reflective of a data cutoff of August 6, 2021 unless otherwise stated. As of an August 6, 2021 data cutoff date, the dose escalation portion of the ongoing Phase 1 trial of PRT543 enrolled a total of 49 patients across 18 unselected advanced solid tumors and lymphoma. Patients enrolled received an average of three prior lines of therapy. PRT543 demonstrated target engagement and inhibition of PRMT5 functional activity as evidenced by a 69% reduction in serum symmetric dimethylarginine, or sDMA, at a dose of 45 mg/5x per week. In addition, PRT543 demonstrated signs of preliminary clinical activity, including a durable CR, maintained for over 18 months in a patient with HRD+ ovarian cancer who remains on treatment and prolonged SD, persisting for over six months in five patients, including four patients with ACC and one patient with uveal melanoma. A complete response is defined as the disappearance of all target lesions.

PRT543 was generally well tolerated: the most common grade 3 or higher treatment-related adverse events, or AE, occurring in at least 5% of patients were thrombocytopenia (27%) and anemia (12%), both of which were reversible upon

treatment interruption. Patients were largely able to remain on therapy with few AE-related dose interruptions (27%), reductions (22%), or discontinuations (4%).

While early in development and there is no guarantee of approval by the FDA or other regulatory authorities, we are encouraged by the clinical activity of PRT543.

Based on data from the ongoing Phase 1 dose expansion studies of both PRT543 and PRT811, we announced, on March 9, 2022, that we are concentrating our development efforts on PRT811 in biomarker-selected patients in specific cancer types. While the Company believes that both PRT811 and PRT543 are high quality, clinically active compounds, PRT811 was selected based on its superior safety profile, higher level of target engagement, and unique brain penetrant properties.

Specifically, we intend to:

PRT811

Overview

Our second PRMT5 inhibitor, PRT811 has completed a Phase 1 dose escalation study and is currently enrolling dose expansion cohorts. PRT811 is designed to be a highly potent, selective and orally bioavailable molecule optimized for high brain exposure and hence we believe is uniquely positioned to treat PRMT5-sensitive CNS cancers among other solid tumors. Data from the expansion cohorts are expected to be presented in the second half of 2022.

Clinical Trial Design and Schema

This is a multicenter, open-label, dose-escalation, dose-expansion Phase 1 clinical trial of PRT811. Enrollment into the dose escalation portion of the clinical trial includes patients with R/R solid tumors, PCNSL, and /or high-grade gliomas. Enrollment initiated in November 2019 and is being conducted across eleven sites in the United States. We initiated enrollment of the dose expansion portion of the clinical trial in three patient cohorts in December 2021. The total expected enrollment is approximately 63 patients.

Figure 2. PRT543 and PRT811 Clinical Trial Schema

Phase 1 Clinical Trial of PRT811

All data are reflective of a data cutoff of August 13, 2021 unless otherwise stated.

The dose escalation portion of the ongoing Phase 1 trial of PRT811 enrolled a total of 45 patients, including 27 patients across 16 unselected advanced solid tumors and 18 patients with high-grade gliomas, including 17 patients with glioblastoma multiforme, or GBM. PRT811 demonstrated dose dependent inhibition of PRMT5 activity as evidenced by an 83% reduction in serum sDMA at a dose of 600 mg daily (QD). In addition, PRT811 demonstrated signs of preliminary clinical activity, including an IDH1 mutated high-grade glioma (glioblastoma (GBM)) patient who experienced a PR that evolved into a durable CR for more than 13 months. In addition, a patient with splicing-mutant, or SF3B1, uveal melanoma demonstrated SD for more than six months with a 25% tumor regression. At a post data-cutoff on September 20, 2021, one additional patient (receiving a dose of 800 mg QD) with SF3B1 uveal melanoma had an unconfirmed PR and 47% decrease in target lesion, and a patient with triple negative breast cancer (receiving a dose of 800 mg QD) demonstrated a 27% decrease in target lesions. PRT811 was generally well-tolerated; the most common grade 3 or higher treatment-related AE was thrombocytopenia (7%), which was reversible upon treatment interruption. Patients were largely able to remain on therapy with few AE-related dose interruptions (13%), reductions (4%), or discontinuations (3%).

Based on data from the ongoing Phase 1 dose expansion studies of both PRT543 and PRT811, we announced on March 9, 2022, that we are concentrating our development efforts on PRT811 in biomarker-selected patients in specific cancer types.

Specifically, we intend to:

MCL1 Inhibitor: PRT1419

Overview

PRT1419 is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. PRT1419 has been optimized to have the PK properties to allow for either oral or IV administration, providing maximal coverage of the target while maintaining an adequate tolerability window. We believe that the physicochemical and pharmacological properties of PRT1419 allow the optionality of administering PRT1419 by either oral or IV route. Based on our preclinical data, as well as published third-party data, we believe that hematological malignancies are particularly sensitive to MCL1 inhibitors. MCL1 upregulation has been noted as a mechanism of acquired resistance to venetoclax and TKIs. In addition, certain solid tumors are responsive to MCL1 inhibition, informing a potential patient selection strategy. Based on data demonstrating that MCL1 is a primary resistance mechanism to BCL2 inhibitors like venetoclax, a combination study with azacitidine or venetoclax in

MDS/AML is planned. The dose escalation portion of the Phase 1 trial of both oral formulation and the IV formulation, which leverages the optimized physicochemical properties of PRT1419, are now underway in patients with solid tumors.

Background

The ability to evade cell death is a hallmark of cancer because it is one of the unique acquired abilities that allows malignant transformation of a normal cell. MCL1 and BCL2 are both members of a family of proteins that regulate cell survival versus cell death. Under normal circumstances, MCL1 and BCL2 exert their pro-survival function by binding to and sequestering the pro-death proteins, BAK and BAX, and prevent the activation of a downstream cascade leading to apoptosis (Figure 3). In normal cells, cellular stressors such as DNA damage disrupt this interaction and result in cell death. Cancer cells, however, frequently upregulate pro-survival proteins to prevent activation of the apoptotic pathway, thus evading death. MCL1 has been shown to have a critical role in promoting cancer cell survival and is frequently found to be amplified or overexpressed in both solid tumors and hematologic cancers.

Figure 3. MCL1 Promotes Tumor Cell Survival by Inhibiting Apoptosis

Members of the BCL2 protein family control cell survival and cell death. MCL1, a member of the family, acts to suppress cell death and has emerged as a target for anti-cancer therapy and as a resistance mechanism to the BCL2 inhibitor, venetoclax.

Inhibition of MCL1 expression and/or function is therefore of considerable therapeutic interest in cancer. The importance of blocking the protein-protein interaction between pro-survival and pro-death proteins as a therapy to promote tumor cell death has been clinically validated with the BCL2 inhibitor, venetoclax. Venetoclax was approved in 2016 for R/R patients with CLL and in 2018 for patients with AML. MCL1 is upregulated in response to BCL2 inhibition and has been implicated in mediating resistance to venetoclax, as well as to chemotherapeutic agents and other targeted therapies including TKIs. These studies have demonstrated the potentially broad clinical benefits of targeting cell survival through MCL1 inhibition in cancer.

Small molecule MCL1 inhibitors have been shown to be remarkably efficacious as monotherapy in preclinical models of MM, AML and lymphoma. Treatment with these inhibitors leads to robust activation of apoptosis markers including cleaved caspase-3 and cleaved PARP in vivo and in vitro. Objective clinical responses were demonstrated in a Phase 1 multiple myeloma clinical trial with AMG176, a third-party MCL1 inhibitor, providing clinical validation of the pathway. MCL1 inhibitors have also demonstrated potent synergistic activity in combination with approved standard of care therapies, including venetoclax, in preclinical models of AML. Although these inhibitors show limited efficacy as monotherapy in solid tumor models, combination with TKIs has resulted in potent anti-tumor effects in triple negative breast cancer, melanoma and non-small cell lung cancer.

Although the data on the importance of MCL1 in driving tumor growth and survival are compelling, complete ablation of MCL1 has been shown to result in cardiomyocyte apoptosis in mice. Mice with heterozygous deletion of Mcl1 resulting in a 50% reduction in MCL1 protein did not demonstrate cardiac abnormalities. These results suggest that an optimized profile for a pharmacological inhibitor of MCL1 should allow for maximal but limited duration of target engagement rather than prolonged coverage to maximize the therapeutic window of MCL1 inhibition in clinical development.

Our Approach to Designing Optimized MCL1 Inhibitors

We used structure-based design to identify PRT1419 as an inhibitor of human MCL1 that is designed to induce tumor cell death by apoptosis. It has been optimized to have high permeability and adequate solubility to provide suitable PK that allows for oral and IV dosing. We believe these features have the potential to maximize the therapeutic window and overcome some of the limitations of current MCL1 inhibitors, as well as provide the convenience and flexibility associated with oral dosing both as monotherapy and potentially in combination with other oral therapies.

PRT1419

Potency and Selectivity

We investigated the in vitro potency of PRT1419 to inhibit the protein-protein interaction of human recombinant MCL1 with the pro-death protein, BIM, by measuring its IC50. In this assay, we observed the IC50 of PRT1419 to be 6.6 nM. We also investigated the in vitro selectivity of PRT1419 for MCL1 as compared to related family members, BCL-2 and BCLXL. We observed that PRT1419 showed >200 times weaker inhibition of BCL-2 and BCLXL compared to MCL1.

Tumor cells undergo apoptosis in response to MCL1 inhibition. Therefore, we investigated the potency of PRT1419 to inhibit the proliferation of cell lines representing both solid tumors and hematologic malignancies. Tumor cell lines were treated with various concentrations of PRT1419 and the number of viable cells was measured after two days in culture. We observed that cell lines representing multiple myeloma, lymphomas and leukemias were particularly sensitive to PRT1419 with IC50 values in the nanomolar range. The in vitro activity of PRT1419 was confirmed in vivo. Once weekly dosing of PRT1419 demonstrated robust efficacy in preclinical models of AML, DLBCL and multiple myeloma.

Clinical Trial Update

Two dose escalation Phase I studies for our oral and IV formulation of PRT1419 are on-going in patients with hematologic malignancies, including patients with high risk myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM. A third dose escalation Phase I study for our IV formulation of PRT1419 is on-going for patients with unselected solid tumors.

On March 9, 2022, we announced that based on the data to date, we intend to prioritize development of the IV formulation of PRT1419, which demonstrated a desirable pharmacokinetic, pharmacodynamic and safety profile with potential for differentiation from competitor compounds. We intend to initiate a combination trial with venetoclax by mid-year with the goal of establishing safety, clinical activity and a recommended Phase 2 dose in the second half of 2022.

CDK9 Program

Overview

CDK9 has emergedas an essentialregulatorof cancer-promotingtranscriptionalprograms,includingthose drivenbyMCL1,MYCandMYB.InhibitionofCDK9 isthusanattractivetherapeuticapproachto produce syntheticlethalityingenomicallyselectedcancers.WehaveappliedourinternalexpertisetodesignPRT2527as apotentinhibitorofCDK9thatexhibitshighkinomeselectivity,PKpropertiesandsolubilitythatwebelieve maybroadenthetherapeuticwindowofCDK9 inhibition.A phase 1 trial is underway evaluating escalating IV doses of PRT2527 as a monotherapy in patients with selected solid tumors, including sarcoma, prostate cancer, lung cancer, and other cancers with genomic alterations that lead to MYC dependence.

Background

Cyclindependentkinases,orCDKs, area familyof closelyrelatedserine/threoninekinasesthathave demonstratedactivityinmultiplecancers.Thefirstinhibitorsoftwoofthefamilymembers,CDK4 andCDK6, gainedFDAapprovalforHR+ metastaticbreastcancerin2015andarenowbroadlyused.IncontrasttoCDK4 andCDK6,whichregulatecellcycleprogressionandproliferation,itisnowappreciatedthatothermembersof theCDKfamilyplayimportantrolesinregulatingtranscription.CDK9 specificallyphosphorylatesRNA polymeraseIItogeneratematuremRNA.Givenitsfundamentalroleintranscription,CDK9 hasemergedasa centralnode in thetranscriptionaladdictionof cancer.

Importantly,inhibitionofCDK9 in cancerhas been shown to preferentiallydepleteshort-livedtranscripts includingkeyanti-apoptoticgenessuchasMCL1andoncogenictranscriptionfactorssuchasMYCandMYB. PreclinicalevidencedemonstratesthatCDK9 inhibitionrepressesMCL1 and therebyovercomesresistanceto the BCL2inhibitorvenetoclax.Additionally,preclinicalstudiessuggestthatCDK9 inhibitionperturbsMYC- mediatedsignalingandproducessyntheticlethalityinnuclearproteinof thetestismidlinecarcinoma, hepatocellularcarcinomaandadditionalsolidtumors.Our patientselectionstrategyin clinicaltrialswould strive toexploitthesesyntheticlethalityrelationshipsbyidentifyingcancerswith molecularevidenceof MCL1 and/or MYC dysregulation.

Our CDK9Inhibitor:PRT2527

Althoughvariousnon-selectiveCDK9 inhibitorshaveprogressedthroughclinicaldevelopment,theyhave beensignificantlylimitedby narrowtherapeuticwindows due to adverseeffects,includingbone marrow suppression,nauseaandGIeffects.Wehave utilizedstructure-baseddesignto identifya novel,structurally differentiatedseriesofCDK9 inhibitors.Iterativesynthesisand testingof over600 compoundsallowedthe identificationofPRT2527,whichhasimprovedpotencyandkinaseselectivitycomparedtoAZ4573, themost advancedCDK9-selectiveinhibitorcurrentlyindevelopment.ThePK andphysicalpropertiesofPRT2527 are suitableforIV or SCdosing.

Inpreclinicalmodels,PRT2527 reducedMCL1andMYC proteinlevelsandwashighlyactivein theMYC- amplifiedMV4-11 xenograftmodelatwell-tolerateddoses. Upon evaluation of additional models, PRT2527 treatment demonstrated robust efficacy in both hematological malignancies and solid tumor models with MYC dysregulation. Our preclinicalstudies suggest that PRT2527 demonstrateshighselectivityandhighpotency,providingopportunityfora widertherapeuticindexcomparedto lessselectiveCDK9inhibitors.

We intend to complete enrollment in the Phase 1 dose escalation study of PRT2527 with the goal of identifying a recommended Phase 2 dose in the second half of 2022.

CDK4/6 Program

Background

Among the CDK subfamily of kinases, CDK4 and CDK6 are the master regulators that control entry of cells into cell cycle. Given the central roles that CDK4 and CDK6 play in cell cycle regulation, dysregulation of the CDK4/CDK6 pathway has been frequently observed in cancer and CDK4/CDK6 have been intensively investigated as potential therapeutic targets for cancer treatment. The approval of three CDK4/CDK6 selective inhibitors in combination with endocrine therapies, to treat hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer has further validated this hypothesis.

Despite the success of CDK4/CDK6 inhibitors for the treatment of ER+ metastatic breast cancer, central nervous system (CNS) diseases such as glioblastoma (GBM) and brain metastases are challenging malignancies with urgent unmet needs. Large scale genomic studies revealed that the CDK4/CDK6 pathway is disrupted in the majority of gliomas, suggesting CDK4/CDK6 may be good targets for GBM. In addition, brain metastases may arise in an estimated 20% of all cancer patients but still lacks effective therapies. Genomic studies also identified the CDK4/6 pathway as one of three most altered and actionable genetic alternations in brain metastasis. However, despite positive preclinical data supporting targeting CDK4/CDK6 to treat CNS cancers, clinical development of CDK4/CDK6 inhibitors for GBM or brain metastases has not been successful, likely due to the inability of current inhibitors to penetrate the blood-brain barrier (BBB) and achieve effective concentrations in the brain.

Our CDK4/6 Inhibitor: PRT3645

Structure based design and iterative compound synthesis and testing led to the identification of PRT3645, a highly brain penetrant molecule that potently and selectively targets CDK4/6. In cellular assays, PRT3645 inhibits phosphorylation of RB, a substrate of CDK4/CDK6, with low nanomolar activity. Consistent with this, PRT3645 treatment results in concentration-dependent inhibition of cell proliferation in glioblastoma (GBM) cell lines and in ER+/HER2- and HER2+ breast cancer lines. In vivo, orally administered PRT3645 was well tolerated and highly efficacious in a dose-dependent manner in orthotopic human breast cancer brain metastasis and GBM models. In a head to head comparison, PRT3645 demonstrated a brain:plasma ratio that was ~100x higher than approved CDK4/6 inhibitors. We plan to complete IND-enabling studies, file an IND and initiate a Phase 1 clinical trial in the second half of 2022.

SMARCA2 (BRM) targeteddegrader program

Background

SMARCA2(alsoknownasBRM)anditsrelatedfamilymember,SMARCA4(alsoknownasBRG1),are theenzymaticsubunitsoftheSWI/SNFcomplexthatregulatesgeneexpressionbyallowingtheDNA tobe accessiblefortranscriptiontomatureRNA,aprocessknownaschromatinremodeling.SMARCA4 ismutatedin multiplecancers,including10-12%ofNSCLC,resultinginlossofSMARCA4protein.Becausetheactivityof eitherSMARCA2 orSMARCA4 isrequiredforchromatinremodelingtooccur,theSMARCA4-deficientcancer cellsbecomehighlydependentonSMARCA2fortheirsurvival.Therefore,webelievetargetingSMARCA2 in SMARCA4-deficientcancerswillproduceastrongsyntheticlethality,resultinginSMARCA4 mutanttumorcell deathwhilesparingnormalcellsthatexpressSMARCA4protein.

Our SMARCA2Degrader Program

DuetothehighhomologybetweenSMARCA2 andSMARCA4, therearefewstructuraldifferencesinthe bindingsitesbetweenthetwoproteinsandthusselectiveSMARCA2 degradationhasbeenachallengefor medicinalchemistry.Targetedproteindegradationisarelativelynewapproachtodegradeoncogenicproteins andhasbeenshowntoprovideselectivedegradationofhighlyhomologousproteins.A moleculecapableof targetingaproteinfordegradation(degrader)typicallycontainsabindingelementtoa targetedproteinof interest (SMARCA2), a chemicallinkerand an E3 ligasebindingelementwhich allowsfortheformationof a ternary complex between the target, the degrader and the E3 ligase that induces ubiquitination and subsequent degradationofthetargetedprotein.Selectivitycanbeachieved,not only by theselectivebindingto thetarget (SMARCA2), butalsothroughtheoptimizationof theuniqueternarycomplexesformedby thetarget (SMARCA2)versusitshomologousprotein(SMARCA4).

Weusedstructure-baseddrugdesigntoidentifyanovelseriesofpotentSMARCA2 degradersthatare outsidethetypicaldrug-likechemicalspace,beingsignificantlylargerand structurallymorecomplex.Extensive structureactivityrelationshipsgeneratedbytheiterativesynthesisandtestingof>700compoundsasofthedate of thisAnnual Report on Form 10-K has allowedtheidentificationof specificstructuralmotifsthat provide >20-fold selectivityfor SMARCA2degradationoverSMARCA4whilemaintainingpotentSMARCA2 degradation,DC50<10nM. DC50isaquantitativemeasureofhowmuchofacompoundisneededtoinhibitthedegradationofaproteinby 50%.WehavedesignedourSMARCA2 degraderstobepotentandselectivetospecificallyinhibitSMARCA4- deficienthumanNSCLCcelllinesandprimarypatientderivedsamples. We are currently profiling our lead compound, PRT-SCA2, and plan to submit an IND application by year-end 2022.

IntellectualProperty

We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the compositions of matter of our product candidates, their methods of use, related technology, and other inventions that are important to our business.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions, and know-how related to our business, to defend and enforce our patents, to preserve the confidentiality of our trade secrets, and to operate without infringing valid and enforceable patents and other

proprietary rights of third parties. We also rely on know-how and continuing technological innovation to develop, strengthen, and maintain our proprietary position in the field of precision oncology.

As more fully described below, our patent portfolio includes, inter alia, patent families with claims directed to compositions of matter for, and methods of using, compounds PRT543, PRT811 PRT1419, PRT2527, PRT3645, and compounds that degrade SMARCA2. The patent portfolio currently comprises of 146 patents and patent applications:

As of the present filing, a total of eight U.S. patents have been issued, which are wholly owned by us. Specifically, a total of three U.S. patent directed to PRT543 have issued and are expected to expire no earlier than August 9, 2038. Similarly, three U.S. patents directed to PRT811 have issued and are expected to expire no earlier than March 14, 2039. Also, one U.S. patent directed to the PRMT5 program has issued and is expected expire no earlier than August 16, 2039. In addition, one U.S. patent directed to PRT1419 has issued and is expected to expire no earlier than November 08, 2039.

In addition to our filings in the United States, we own patent applications that are pending in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine. Included in these applications are claims directed to the PRT543, PRT811, and PRT1419 composition and methods of using the same therapeutically. For the PRT543 compound, the patents from these applications, if issued, are expected to expire in August 2038, subject to any disclaimers or extensions. For the PRT811 compound, the patents from these applications, if issued, are expected to expire in March 2039, subject to any disclaimers or extensions. For the PRT1419 compound, the patents from these applications, if issued, are expected to expire in November 2039, subject to any disclaimers or extensions.

The patent portfolios for our most advanced programs are summarized below.

PRT543

OurPRT543patentportfolioiswhollyownedbyus.TheportfolioincludesthreeissuedU.S. patents,which claim,amongotherthings,PRT543,pharmaceuticalcompositionscomprisingPRT543,methodsofinhibiting PRMT5 usingPRT543, andmethodsoftreatingcertaincancers,includingbreastand ovariancancers,using PRT543.TheseU.S. patents areexpectedtoexpirenoearlierthanAugust9,2038, subject to any disclaimers or extensions available, including under the Hatch-Waxman Act. Corresponding patent applications are pending in several other countries and regions, including Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine. Any patents resulting from these patent applications, if issued, are also expected to expire no earlier than August 9, 2038, subject to any disclaimers or extensions.

ThePRT543patentportfolioalsoincludesfourpendingU.S.andonependingPCTpatentapplications, whichclaim,amongotherthings,agenusofcompoundsthatencompassPRT543, PRT543 saltsandcrystalline forms,methodsofpreparingPRT543,andadditionalmethodsoftreatmentusingPRT543.AnyU.S. patents issuingfromtheseapplicationswouldbeexpectedtoexpireno earlier than August 9, 2038, August 13, 2041; October 5, 2041; 9 and December 9, 2041, respectively, subject to any disclaimers or extensions.

The PRT543 patent portfolio also includes six pending U.S. provisional applications that relate to among other things,methodsofinhibiting PRMT5usingPRT543,methodsoftreatingcertaincancers, and associated clinical studies. Any patents granted that claim priority to this provisional application could expire as late as 2042.

PRT811

OurPRT811patentportfolioiswhollyownedbyus.TheportfolioincludesthreeissuedU.S. patents,which claim,amongotherthings,PRT811,pharmaceuticalcompositionscomprisingPRT811,methodsofinhibiting PRMT5usingPRT811,andmethodsoftreatingcertaincancers,includingglioblastoma,usingPRT811. The patents areexpectedtoexpirenoearlierthanMarch14, 2039, subjectto any disclaimersor extensionsavailable under the Hatch-Waxman Act. A related

PCT application was filed, and corresponding national phase applicationswerefiledinAustralia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.Anypatentsresultingfromthesenationalpatentapplications,ifissued, areexpectedto expireno earlierthanMarch14, 2039, subjectto any disclaimersor extensions.

ThePRT811 patentportfolioalsoincludestwopendingU.S. non-provisionalapplications and two PCT applicationsthatclaimcompositionsofmatter,andsmethodsoftreatment. Anypatentsissuingfromtheone pendingU.S.non-provisionalapplicationwould be expectedto expireno earlier than April 03, 2020, andanypatentsissuingfromthetwoPCT applicationswouldbeexpectedtoexpirenot earlier than 2039 and 2040respectively,subjecttoany disclaimersor extensions.

The PRT811 patent portfolio also includes three pending U.S. provisional applications that relate to among other things,methodsofinhibiting PRMT5usingPRT811,andmethodsoftreatingcertaincancers, and associated clinical studies. Any patents granted that claim priority to this provisional application could expire as late as 2042.

PRT1419

OurPRT1419 patentportfolio,whichiswhollyownedbyus. The portfolio includes one issued U.S. patent, which claims amongotherthings,PRT1419 and othercompounds,pharmaceuticalcompositionscomprising PRT1419,andmethodsofusingsuch compounds. The patent isexpectedtoexpirenoearlierthanNovember 8, 2039, subjectto any disclaimersor extensionsavailable under the Hatch-Waxman Act. A related PCT application was filed, and corresponding national phase applicationswerefiledinAustralia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, South Africa, South Korea, and Ukraine.Anypatentsresultingfromthesenationalpatentapplications,ifissued, areexpectedto expireno earlierthanNovember 08, 2039, subjectto any disclaimersor extensions.

The portfolio also included one pendingU.S. non-provisional patentapplication, which claims amongotherthings,PRT1419 related compounds,pharmaceuticalcompositionscomprising PRT1419 related compounds,andmethodsofusingsuch compounds. Anypatentsissuedfromthisapplicationwouldbeexpectedtoexpire noearlierthanAugust 17, 2041, subjecttoanydisclaimersorextensions.

PRT2527

OurPRT2527 patentportfolio,whichiswhollyownedbyus,includesoneU.S. non-provisionalpatent applicationandonePCT applicationclaiming,amongotherthings,PRT2527 andothercompounds, pharmaceuticalcompositionscomprisingPRT2527,and methodsof usingPRT2527.Any patentsthatissuebased upontheseU.S.non-provisionalandPCTapplicationswouldbeexpectedtoexpirenoearlierthan2040,subject to any disclaimersor extensions.

The PRT2527 patent portfolio also includes two pending U.S. provisional applications that relate to among other things,methodsofinhibiting CDK9usingPRT2527 related compoundsandmethodsoftreatingcertaincancers. Any patents granted that claim priority to this provisional application could expire as late as 2041.

PRT3645

Our PRT3645 patent portfolio, which is wholly owned by us, includes two pending U.S. non-provisional patent applications and two corresponding PCT applications claiming, among other things, genera of compounds that encompass PRT3645 and other compounds, and/or related inhibitors, pharmaceutical compositions comprising those inhibitors, and methods of treating cancer with those inhibitors. Any patents issued from the U.S. patent applications would be expected to expire no earlier than September 21, 2041, and December 17, 2041, respectively, subject to any disclaimers or extensions available under the Hatch-Waxman Act.

The PRT3645 patent portfolio also includes two pending U.S. provisional applications that, among other things,encompassPRT3645 and/orrelated CDKinhibitors,pharmaceuticalcompositionscomprisingthoseinhibitors,and methodsof treatingcancerwith thoseinhibitors. Any patents granted that claim priority to this provisional application could expire as late as 2042.

SMARCA2Degraders

TheSMARCA2 degraderpatentportfolioincludestwopendingnon-provisionalU.S. applications and two corresponding PCT applications,which claim,amongotherthings,generaof compoundsthat encompassSMARCA2 and/orrelatedinhibitors,pharmaceuticalcompositionscomprisingthoseinhibitors,and methodsof treatingcancerwith thoseinhibitors. Anypatentsissuedfrom the U.S. patent applications wouldbeexpectedtoexpire noearlierthan June 09, 2041 andNovember 08, 2041, respectively, subjecttoanydisclaimersorextensions available under the Hatch-Waxman Act.

The SMARCA2 patent portfolio also includes one pending U.S. provisional application that, among other things,encompassSMARCA2 and/orrelatedinhibitors,pharmaceuticalcompositionscomprisingthoseinhibitors,and methodsof treatingcancerwith thoseinhibitors. Any patents granted that claim priority to this provisional application could expire as late as 2042.

Other

Inaddition,we have patentportfoliosthataredirectedto a numberof differentcompoundsotherthan PRT543,PRT811,PRT1419,PRT2527, PRT3645, SMARCA2 degraders, and CDK inhibitors.Wehavepatentapplicationsdirectedto compoundsthattargetresistancemechanismsin cancer.We expectto maintainsomeof theseapplicationsin the UnitedStatesand to alsofilein foreigncountries.

In additionto theapplicationsdescribedabove, we wholly-own 16applicationsincludingU.S. provisionalpatentapplications,U.S. non-provisionalpatentapplications,andPCTapplications,coveringcompositionsandmethodsofmakingandusingthosecompounds to treatcancerand otherdiseases.

The termof individualpatentsdependsupon thelegaltermof thepatentsin thecountriesin which theyare obtained.Inthecountriesinwhichwefile,thepatenttermis20yearsfromtheearliestnon-provisionalfiling date,subjecttoanydisclaimersorextensions.ThetermofapatentintheUnitedStatescanbeadjusteddueto anyfailureoftheUnitedStatesPatentandTrademarkOfficefollowingcertainstatutoryand regulationdeadlines forissuinga patent.

In theUnitedStates,thepatenttermof a patentthatcoversan FDA-approved drug mayalsobe eligiblefor patenttermextension,whichpermitspatenttermrestorationascompensationfora portionof thepatenttermlost duringtheFDAregulatoryreviewprocess.TheHatch-WaxmanActpermitsapatenttermextensionofupto fiveyearsbeyondtheoriginalexpirationofthepatent.Theprotectionprovidedby a patentvariesfromcountryto country,andisdependentonthetypeofpatentgranted,thescopeofthepatentclaims,and thelegalremedies availablein a givencountry.

Obtainingpatentprotectionisnottheonlymethodthatwe employto protectour proprietaryrights.We also utilizeotherformsofintellectualpropertyprotection,includingtrademark,copyright,and tradesecrets,when thoseotherformsarebettersuitedtoprotectaparticularaspectofourintellectualproperty.Our beliefisthatour proprietaryrightsarestrengthenedby our comprehensiveapproachto intellectualproperty protection.It is our policytorequireouremployees,consultants,outsidescientificcollaborators,sponsoredresearchersandother advisorstoexecuteconfidentialityagreementsuponthecommencementofemploymentor consulting relationshipswithus.Theseagreementsprovidethatallconfidentialinformationconcerningour businessor financialaffairsdevelopedormadeknowntotheindividualduringthecourseoftheindividual’srelationship withusistobekeptconfidentialandnotdisclosedto thirdpartiesexceptin specificcircumstances.In thecaseof employees,theagreementsprovidethatallinventionsconceivedby theindividual,and which arerelatedto our currentorplannedbusinessorresearchanddevelopmentormadeduringnormalworkinghours,onour premises or usingour equipmentor proprietaryinformation,areour exclusiveproperty.

Manufacturing

Wedonotownoroperate,andcurrentlyhavenoplansto establish,any manufacturingfacilities.We currentlyrely,andexpecttocontinuetorelyfortheforeseeablefuture,on thirdpartiesforthemanufactureof our productcandidatesforpreclinicaland clinicaltesting,includingpharmaceuticalingredientsand clinicaldrug supply,aswellasforcommercialmanufactureofany drugsthatwe maycommercialize.We obtainour supplies fromthesemanufacturersonapurchaseorderbasisanddonot have long-termsupplyarrangementsin place.We donotown in-housewarehousefacilities.We relyon thirdpartiesforstorageand distributionof drug substance and drug product.We do not currentlyhave arrangementsin place

forredundantsupplyforactivepharmaceutical ingredientsanddrugproduct.Asour developmentprogramsprogressand we buildnew processefficiencies,we expecttocontinuallyevaluatethisstrategywiththeobjectiveof satisfyingdemandforregistrationtrialsand, if approved,themanufacture,saleand distributionof commercialproducts.

Commercialization

Givenourstageofdevelopment,we have not yetestablisheda commercialorganizationor distribution capabilities.Ifwearesuccessfulinobtainingnecessaryregulatoryapproval,wemaypursuecommercialization on our own or seekto collaboratewith a thirdpartyforcommercialization,particularlyoutsidetheUnitedStates.

Thebiotechnologyandpharmaceuticalindustriesarecharacterizedbytherapidevolutionoftechnologies and understandingof diseaseetiology,intensecompetitionand a strongemphasison intellectualproperty. We believethatourapproach,strategy,scientificcapabilities,know-howandexperienceprovideus with competitive advantages.However, we expectsubstantialcompetitionfrommultiplesources,includingmajor pharmaceutical, specialtypharmaceutical,and existingor emergingbiotechnologycompanies,academicresearchinstitutionsand governmentalagenciesand publicand privateresearchinstitutionsworldwide.Many of our competitors,either aloneorthroughcollaborations,have significantlygreaterfinancialresourcesand expertisein researchand development,manufacturing,preclinicaltesting,conducting clinicaltrials,obtaining regulatoryapprovals and marketingapprovedproductsthanwe do. Smalleror early-stagecompaniesmayalsoproveto be significant competitors,particularlythroughcollaborativearrangementswithlargeand establishedcompanies.These competitorsalsocompetewith us in recruitingand retainingqualifiedscientificand managementpersonneland establishingclinicaltrialsitesand patientenrollmentin clinicaltrials,as wellas in acquiringtechnologies complementaryto, or necessaryfor,our programs.As a result,our competitorsmay discover, develop, licenseor commercializeproductsbeforeor moresuccessfullythanwe do.

Competition

We facecompetitionfromsegmentsof thepharmaceutical,biotechnologyand other relatedmarketsthat pursuethedevelopmentofprecisiononcologytherapiesoptimizedtotargetthekey drivermechanismsin cancers withhighunmetneed. Severalbiopharmaceuticalcompanies,includingArvinas Inc., Aurigene, Black DiamondTherapeutics,Inc., Boehringer Ingelheim, C4 Therapeutics, ConstellationPharmaceuticals,Inc., Eli Lilly and Company, F. Hoffman-La Roche, Foghorn Therapeutics Inc., Fochon Pharmaceuticals, G1 Therapeutics Inc., Genentech, Kronos Bio, Inc., Kura Oncology, Inc., Kymera Therapeutics Inc., Mirati Therapeutics Inc., Nuvation Bio Inc. RepareTherapeuticsInc.,RevolutionMedicines,Inc., Relay Therapeutics,Inc., Springworks Therapeutics, Inc., Syndax Pharmaceuticals, Inc., and ZentalisPharmaceuticals,Inc.,aredevelopingprecisiononcologymedicines.In addition,wemayfacecompetitionfromcompaniesdevelopingproductcandidatesthatarebasedontargeting pathwaysofadaptiveresistance,includingAmgen Inc., AbbVie Inc., AstraZeneca plc,GlaxoSmithKline plc,Ideaya Biosciences, Johnson & Johnson Services, Inc., Pfizer Inc., Tango Therapeutics, Inc., Vincerx Pharma, Inc., Novartis AG, and Gilead Sciences, Inc.

Furthermore,we also face competitionmore broadly across the oncology marketfor cost-effectiveand reimbursable cancertreatments. The most common methods of treating patients with cancer are surgery, radiationanddrugtherapy,includingchemotherapy,hormonetherapy,biologictherapy,such as monoclonaland bispecificantibodies,immunotherapy,cell-basedtherapyand targetedtherapy,or a combinationof any such methods.Therearea varietyof availabledrug therapiesmarketedforcancer.In manycases,thesedrugsare administered incombinationtoenhanceefficacy.Whileourproductcandidates,ifanyareapproved,may competewiththeseexistingdrugsandothertherapies,to theextenttheyareultimatelyused in combinationwith orasanadjuncttothesetherapies,ourproductcandidatesmaynotbecompetitivewiththem.Someofthese drugsarebrandedandsubjectto patentprotection,and othersareavailableon a genericbasis.Insurersand other third-partypayorsmayalsoencouragetheuseofgenericproductsorspecificbrandedproducts.Asa result, obtainingmarketacceptanceof,andgainingsignificantshareofthemarketfor,anyofourproductcandidates thatwe successfullyintroduceto themarketmaypose challenges.In addition,many companiesare developing newoncologytherapeutics,andwecannotpredictwhatthestandardofcarewillbe as our productcandidates progressthroughclinicaldevelopment.

With respect to our PRMT5 programs, PRT543 and PRT811, several companies are developing PRMT5 inhibitors with clinical trials ongoing, including Amgen (AMG193), GlaxoSmithKline (GSK3326595), Ideaya Biosciences (IDE397),

Johnson & Johnson (JNJ-64619178), Pfizer (PF-06939999), and Tango Therapeutics (TNG908). For our product candidate PRT1419, other companies are developing MCL1 inhibitors with monotherapy and/or combination trials ongoing, including Amgen (AMG176), AstraZeneca (AZD5991), Novartis (MIK665), and Gilead (GS-9716). For our CDK9 program, PRT2527, AstraZeneca (AZD4573), Vincerx (VIP512), and Kronos (KB-0742) have CDK9 programs in Phase 1 clinical trials. For our CDK4/6 inhibitor program, PRT3645 Novartis (ribociclib), Lilly (abemaciclib), Pfizer (palbociclib), G1 Therapeutics (G1T38), and Fochon Pharmaceuticals (FCN-437) have clinical trials ongoing. For our SMARCA 2 (BRM) degrader program, other companies, including Amgen, Aurigene, C4 Therapeutics, F. Hoffman-La Roche, Foghorn Therapeutics, Inc.,KymeraTherapeutics,Arvinas, Genentech, Boehringer Ingelheim, and Lilly have publicly disclosed their pre-clinical research efforts.

Wecouldseeareductionor eliminationin our commercialopportunityifour competitorsdevelopand commercializedrugsthataresafer,moreeffective,have feweror lesssevereside effects,are more convenient to administer,arelessexpensiveorwithmorefavorablelabelingthanourproductcandidates.Our competitorsalso mayobtainFDA orotherregulatoryapprovalfortheirdrugsmorerapidlythanwemayobtainapprovalforours, whichcouldresultinourcompetitorsestablishingastrongmarketpositionbeforeweareabletoenterthe market.The key competitivefactorsaffectingthesuccessof allof our productcandidates,if approved, are likely tobe theirefficacy,safety,convenience,price,thelevelof genericcompetitionand theavailabilityof reimbursementfromgovernmentand otherthird-partypayors.

GovernmentRegulation

GovernmentauthoritiesintheUnitedStates,atthefederal,stateandlocallevel,and in othercountriesand jurisdictionsextensivelyregulate,among other things, the research,development,testing,manufacture, quality control, approval, packaging, storage, recordkeeping,labeling,advertising,promotion,distribution,marketing, post-approvalmonitoringandreporting,andimportandexportof pharmaceuticalproducts.The processesfor obtainingregulatoryapprovalsin theUnitedStatesand in foreigncountriesand jurisdictions,alongwith subsequentcompliancewithapplicablestatutesand regulationsand otherregulatoryauthorities,requirethe expenditureof substantialtimeand financialresources.

FDAApproval Process

IntheUnitedStates,pharmaceuticalproductsaresubjecttoextensiveregulationby theFDA, TheFederalFood,Drug,andCosmeticAct,orFD&C Act,andotherfederalandstate statutesand regulationsgovern,amongotherthings,theresearch,development,testing,manufacture,storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting,samplingandimportand exportof pharmaceuticalproducts.Failureto complywith applicableU.S. requirementsmaysubjectacompanyto a varietyof administrativeor judicialsanctions,such as clinicalhold, FDArefusaltoapprovependingNDAs, warningoruntitledletters,productrecalls,productseizures,totalor partialsuspensionof productionor distribution,injunctions,fines,civilpenaltiesand criminalprosecution.

Pharmaceuticalproductdevelopmentforanewproductorcertainchangestoanapprovedproductinthe U.S. typicallyinvolvespreclinicallaboratoryandanimaltests,thesubmissiontoFDA ofaninvestigationalnew drugapplication,orIND,whichmustbecomeeffectivebeforeclinicaltestingmaycommence,and adequateand well-controlledclinicaltrialstoestablishthesafetyand effectivenessof thedrug foreachindicationforwhich FDA approvalissought.SatisfactionofFDA pre-marketapprovalrequirementstypicallytakesmanyyearsand theactualtimerequiredmayvarysubstantiallybasedupon thetype,complexityand noveltyof theproductor disease.

Preclinicaltestsincludelaboratoryevaluationof productchemistry,formulationand toxicity,as wellas animaltrialstoassessthecharacteristicsand potentialsafetyand efficacyof theproduct.The conductof the preclinicaltestsmustcomplywith federalregulationsand requirements,includinggood laboratorypractices.The resultsofpreclinicaltestingaresubmittedtoFDA aspartofanINDalongwithotherinformation,including informationaboutproductchemistry,manufacturingand controls,and a proposedclinicaltrialprotocol.Long- termpreclinicaltests,suchasanimaltestsofreproductivetoxicityand carcinogenicity,maycontinueafterthe INDissubmitted.A30-daywaitingperiodafterthesubmissionof eachIND isrequiredpriorto the commencementofclinicaltestinginhumans.IfFDA hasneithercommentedonnorquestionedtheIND within this30-dayperiod,theclinicaltrialproposedin theIND may begin. Clinicaltrialsinvolve the administrationof theinvestigationalnewdrugtohealthyvolunteersorpatientsunderthesupervisionof a qualifiedinvestigator. Clinicaltrialsmustbeconducted:(i)in compliancewith federalregulations;(ii)in compliancewith good

clinical practice,orGCP,aninternationalstandardmeanttoprotecttherightsandhealthofpatientsandtodefinethe rolesofclinicaltrialsponsors,administratorsandmonitors;aswellas(iii)underprotocolsdetailingthe objectivesofthetrial,theparameterstobeusedinmonitoringsafetyandtheeffectivenesscriteriatobe evaluated.EachprotocolinvolvingtestingonU.S. patientsandsubsequentprotocolamendmentsmustbe submittedto FDAas partof theIND.

FDA mayorderthetemporary,orpermanent,discontinuationofaclinicaltrialatany time,or imposeother sanctions,ifitbelievesthattheclinicaltrialeitherisnotbeingconductedinaccordancewithFDArequirements orpresentsanunacceptablerisktotheclinicaltrialpatients.Impositionofaclinicalholdmaybe fullor partial. Thestudyprotocolandinformedconsentinformationforpatientsin clinicaltrialsmustalsobe submittedto an institutionalreviewboard,or IRB, and ethicscommitteeforapproval.The IRB willalso monitorthe clinicaltrial untilcompleted.An IRB mayalsorequiretheclinicaltrialatthesiteto be halted,eithertemporarilyor permanently,forfailureto complywith theIRB’s requirements,or mayimposeotherconditions.Additionally, someclinicaltrialsareoverseenbyanindependentgroup of qualifiedexpertsorganizedby theclinicaltrial sponsor,knownasadatasafetymonitoringboardor committee.This group providesauthorizationforwhethera trialmaymoveforwardatdesignatedcheckpointsbasedon accessto certaindatafromthetrial.

ClinicaltrialstosupportNDAsformarketingapprovalaretypicallyconductedinthreesequentialphases, butthephasesmayoverlap.InPhase1,theinitialintroductionofthedrugintohealthyhumansubjectsor patients,thedrugistestedto assessmetabolism,pharmacokinetics,pharmacologicalactions,sideeffects associatedwithincreasingdoses,and,ifpossible,earlyevidenceof effectiveness.Phase 2 usuallyinvolvestrials in a limitedpatientpopulationto determinetheeffectivenessof thedrug fora particularindication,dosage toleranceandoptimumdosage,andtoidentifycommonadverseeffectsandsafetyrisks.Ifa drug demonstrates evidenceofeffectivenessandanacceptablesafetyprofileinPhase 2 evaluations,Phase 3 trialsareundertakento obtaintheadditionalinformationaboutclinicalefficacyandsafetyinalargernumberofpatients,typicallyat geographicallydispersedclinicaltrialsites,topermitFDA toevaluatetheoverallbenefit-riskrelationshipofthe drugandtoprovideadequateinformationforthelabelingofthedrug.InmostcasesFDA requirestwoadequate andwell-controlledPhase3clinicaltrialstodemonstratetheefficacyofthedrug.AsinglePhase3trialmaybesufficientinrareinstances, including (1) wherethestudyisalargemulticenter trialdemonstratinginternalconsistencyandastatisticallyverypersuasivefindingofaclinicallymeaningful effectonmortality,irreversiblemorbidityor preventionof a diseasewith a potentiallyseriousoutcomeand confirmationof theresultin a secondtrialwould be practicallyor ethicallyimpossible or (2) when in conjunction with other confirmatory evidence.

ThesePhasesmayoverlaporbecombined.Forexample,aPhase1/2clinicaltrialmaycontainbotha dose- escalationstageandadose-expansionstage,thelatterofwhichmayconfirmtolerabilityattherecommended doseforexpansioninfutureclinicaltrials(asintraditionalPhase1clinicaltrials)andprovideinsightintothe anti-tumoreffectsof theinvestigationaltherapyin selectedsubpopulation(s).

Typically,duringthedevelopmentof oncologytherapies,allsubjectsenrolledin Phase 1 clinicaltrialsare disease-affectedpatientsand, as a result,considerablymoreinformationon clinicalactivitymaybe collected duringsuchtrialsthanduringPhase1clinicaltrialsfornon-oncologytherapies.Asinglepivotaltrialmaybe sufficientinrareinstancestoprovidesubstantialevidenceofeffectiveness(generallysubjecttotherequirement of additionalpost-approvalstudies).

ThemanufacturerofaninvestigationaldruginaPhase2or3clinicaltrialfora seriousor life-threatening diseaseisrequiredtomakeavailable,suchasbypostingonitswebsite,itspolicyonevaluatingandresponding to requestsforexpandedaccess.

Aftercompletionoftherequiredclinicaltesting,anNDA ispreparedandsubmittedtoFDA. FDA approval oftheNDAisrequiredbeforemarketingoftheproductmaybeginintheU.S. TheNDA mustincludetheresults ofallpreclinical,clinicalandothertestinganda compilationof datarelatingto theproduct’spharmacology, chemistry,manufactureand controls.

ThecostofpreparingandsubmittinganNDAissubstantial.ThesubmissionofmostNDAs isadditionally subjecttoasubstantialapplicationuserfee.Fee waiversor reductionsareavailablein certaincircumstances, includingawaiveroftheapplicationfeeforthefirstapplicationfiledby a smallbusiness.Additionally,no user feesareassessedonNDAsforproductsdesignatedasorphandrugs,unlesstheproductalsoincludesanon-orphanindication.Theapplicantunderan

approvedNDA isalsosubjectto annualprogramfees.The FDA adjuststheuserfeeson an annualbasis,and thefeestypicallyincreaseannually.

FDA reviewseachsubmittedNDA beforeitdetermineswhethertofileit, based on the agency’s threshold determination that it is sufficiently complete to permit substantive review, and FDA mayrequestadditional information.TheFDA mustmakeadecisiononwhethertofileanNDA within60daysofreceipt,andsuch decisioncouldincludearefusaltofilebytheFDA.Oncethesubmissionisfiled,FDA beginsanin-depthreview oftheNDA.FDA hasagreedtocertainperformancegoalsinthereviewofNDAs. Mostapplicationsforstandard reviewdrug productsarereviewedwithintento twelve months; most applicationsfor priorityreview drugs are reviewedinsixtoeightmonths.PriorityreviewcanbeappliedtodrugsthatFDAdeterminesoffermajor advancesintreatmentorprovideatreatmentwherenoadequatetherapyexists.The reviewprocessforboth standardandpriorityreviewmaybeextendedbyFDA forthreeadditionalmonthstoconsidercertainlate- submittedinformation,orinformationintendedtoclarifyinformationalreadyprovidedinthesubmission.The FDAdoesnotalwaysmeetitsgoaldatesforstandardandpriorityNDAs, andthereviewprocesscanbeextended by FDArequestsforadditionalinformationor clarification.

FDA mayalsoreferapplicationsfornoveldrugproducts,ordrugproductsthatpresentdifficultquestionsof safetyorefficacy,toanoutsideadvisorycommittee—typicallyapanelthatincludescliniciansand other experts—forreview,evaluationand a recommendationas to whethertheapplicationshouldbe approved and underwhatconditions,ifany.FDA isnot bound by therecommendationof an advisorycommittee,but it generallyfollowssuch recommendations.

BeforeapprovinganNDA,FDAwillconductapre-approvalinspectionofthemanufacturingfacilitiesfor thenewproducttodeterminewhethertheycomplywithcGMPrequirements.FDA willnotapprovetheproduct unlessitdeterminesthatthemanufacturingprocessesand facilitiesarein compliancewith cGMP requirements and adequate to assure consistent production of the product within required specifications. The FDAalso typicallyinspectsoneormoreclinicaltrialsitestoensurecompliancewithGCP requirementsandtheintegrityof thedatasupportingsafetyand efficacy.

AfterFDA evaluatestheNDA andthemanufacturingfacilities,itissueseitheranapprovalletteror a complete response letter. A complete response letter, or CRL, generally outlines the deficiencies in the submissionandmayrequiresubstantialadditionaltesting,orinformation,inorderforFDA toreconsiderthe application,suchasadditionalclinicaldata,additionalpivotalclinicaltrial(s),and/orothersignificantand time- consumingrequirementsrelatedtoclinicaltrials,preclinicalstudiesormanufacturing.IfaCRLisissued,the applicantmayresubmittheNDA addressingallofthedeficienciesidentifiedin theletter,withdrawthe application,engageinformaldisputeresolutionorrequestanopportunityforahearing.FDA hascommittedto reviewingresubmissionsintwo or sixmonthsdependingon thetypeof informationincluded.Even ifsuch data and informationaresubmitted,theFDAmaydecidethattheNDAdoes not satisfythecriteriaforapproval.

If,orwhen,thedeficienciesidentifiedintheCRL havebeenaddressedtoFDA’ssatisfactionina resubmissionoftheNDA, FDA willissueanapprovalletter.Anapprovalletterauthorizescommercialmarketing ofthedrugwithspecificprescribinginformationforspecificindications.AsaconditionofNDA approval,FDA mayrequireariskevaluationandmitigationstrategy,orREMS, tohelpensurethatthebenefitsof thedrug outweighthepotentialriskstopatients.AREMS canincludemedicationguides,communicationplansfor healthcareprofessionals,andelementstoassuresafeuse,orETASU. ETASU caninclude,butarenotlimitedto, special training or certification for prescribing ordispensing, dispensing onlyunder certain circumstances, specialmonitoring,andtheuseofpatientregistries.TherequirementforaREMS canmateriallyaffectthe potentialmarketandprofitabilityof thedrug. Moreover,productapprovalmayrequiresubstantialpost-approval testingand surveillanceto monitorthedrug’ssafetyor efficacy.Once granted,productapprovalsmay be withdrawnifcompliancewith regulatorystandardsisnot maintainedor problemsareidentifiedfollowing initial marketing.

Changestosomeoftheconditionsestablishedinanapprovedapplication,includingchangesin indications, labeling,ormanufacturingprocessesorfacilities,requiresubmissionandFDA approvalofanNDA supplement or,insomecase,anewNDA, beforethechangecanbeimplemented.AnNDA supplementfora new indication typicallyrequiresclinicaldatasimilartothatintheoriginalapplication,andFDA usesthesameproceduresand actionsin reviewingNDAsupplementsas itdoes in reviewingNDAs.

Disclosureof ClinicalTrialInformation

SponsorsofclinicaltrialsofFDA regulatedproducts,includingdrugs,arerequiredtoregisteranddisclose certainclinicaltrialinformation.Informationrelatedtotheproduct,patientpopulation,phaseofinvestigation, studysitesandinvestigators,andotheraspectsof theclinicaltrialisthenmadepublicas partof theregistration. Sponsorsarealsoobligatedtodiscusstheresultsoftheirclinicaltrialsaftercompletion.Disclosureof theresults ofthesetrialscanbe delayedin certaincircumstancesforup to two yearsafterthedateof completionof thetrial. Competitors may use this publicly available information to gain knowledge regarding the progress of developmentprograms.

ExpeditedDevelopmentand Review Programs

Fast Track Designation

Fasttrackdesignationmaybe grantedfora productthatisintendedto treata seriousor life-threatening diseaseor conditionforwhich thereisno effectivetreatmentand preclinicalor clinicaldata demonstratethe potentialtoaddressunmetmedicalneedsforthecondition.Thesponsorofan investigationaldrug productmay requestthatFDA designatetheproductcandidateforaspecificindicationasa fasttrackdrug concurrentwith, or after,thesubmissionoftheINDfortheproductcandidate.FDAmustdetermineiftheproductcandidate qualifiesforfasttrackdesignationwithin60daysofreceiptofthesponsor’srequest.Forfasttrackproducts, sponsorsmayhavegreaterinteractionswiththeFDA andtheFDA mayinitiatereviewofsectionsofa fasttrack product’sNDAbeforetheapplicationiscomplete.This“rollingreview”isavailableiftheFDA determines,after preliminaryevaluationofclinicaldatasubmittedbythesponsor,thatafasttrackproductmaybeeffective.The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining informationandthesponsormustpayapplicableuserfees.AtthetimeofNDA filing,theFDA willdetermine whethertograntpriorityreviewdesignation.FDA willgrantsuchdesignationiftheproposeddrugwouldbea significantimprovementinthesafetyor effectivenessof thetreatment,prevention,or diagnosisof a serious condition.Additionally,fasttrackdesignationmaybewithdrawnifFDAbelievesthatthedesignationisno longersupportedby dataemergingin theclinicaltrialprocess.

AcceleratedApproval

Acceleratedapprovalmaybegrantedforaproductthatisintendedtotreata seriousor life-threatening conditionandthatgenerallyprovidesa meaningfultherapeuticadvantageto patientsoverexistingtreatments.A producteligibleforacceleratedapprovalmaybe approvedon thebasisof eithera surrogateendpointthatis reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversiblemorbidityormortality,thatisreasonablylikelytopredictaneffecton irreversiblemorbidityor mortalityorotherclinicalbenefit,takingintoaccounttheseverity,rarityorprevalenceoftheconditionand the availabilityorlackofalternativetreatments.The acceleratedapprovalpathway ismostoftenused in settingsin whichthecourseofadiseaseislongandan extendedperiodof timeisrequiredto measuretheintendedclinical benefitofaproduct,eveniftheeffecton thesurrogateor intermediateclinicalendpointoccursrapidly.Thus, acceleratedapprovalhasbeenusedextensivelyin thedevelopmentand approvalof productsfortreatmentof a varietyof cancersin which thegoalof therapyisgenerallyto improvesurvivalor decreasemorbidityand the durationof thetypicaldiseasecourserequireslengthyand sometimeslargestudiesto demonstratea clinicalor survivalbenefit.The acceleratedapprovalpathway iscontingenton a sponsor’sagreementto conduct additional post-approvalconfirmatorystudiestoverifyanddescribetheproduct’sclinicalbenefit.These confirmatorytrials mustbecompletedwithduediligenceand,inmostcases,theFDAmayrequirethatthetrialbedesigned, initiated,and/orfullyenrolledpriortoapproval.Failuretoconductrequiredpost-approvalstudies,ortoconfirm aclinicalbenefitduringpost-marketingstudies,wouldallowtheFDAtowithdrawtheproductfromthemarket onanexpeditedbasis.Allpromotionalmaterialsforproductcandidatesapprovedunderacceleratedregulations aresubjectto priorreviewby theFDA.

BreakthroughTherapy Designation

FDA isalsorequiredtoexpeditethedevelopmentandreviewofapplicationsforapprovalofdrugsthatare intendedtotreata seriousor life-threateningdiseaseor conditionwhere preliminaryclinicalevidenceindicates thatthedrugmaydemonstratesubstantialimprovementoverexistingtherapiesonone or moreclinically significantendpoints.Under thebreakthroughtherapyprogram,thesponsorof a new productcandidatemay requestthatFDA designatetheproductcandidateforaspecificindicationasabreakthroughtherapyconcurrent with,orafter,thefilingoftheINDfortheproductcandidate.FDA mustdetermineiftheproductcandidate qualifiesforbreakthroughtherapydesignationwithin60daysofreceiptofthesponsor’srequest.TheFDA may takecertainactionswith respectto breakthroughtherapies,includingholding

meetingswith thesponsor throughoutthedevelopmentprocess,providingtimelyadviceto theproductsponsorregardingdevelopmentand approval,involvingmoreseniorstaffinthereviewprocess,assigningacross-disciplinaryprojectleadforthe reviewteamand takingotherstepsto designtheclinicalstudiesin an efficientmanner.

OrphanDrugs

UndertheOrphanDrugAct,FDAmaygrantorphandrugdesignationtodrugsintendedtotreatarare diseaseorcondition,whichisgenerallyadiseaseor conditionthataffectsfewerthan200,000 individualsin the UnitedStates,ormorethan200,000 individualsin theUnitedStatesbut forwhich thereisno reasonable expectationthatthecostofdevelopingandmakingtheproductforthistypeof diseaseor conditionwillbe recoveredfromsalesof theproductin theUnitedStates.

OrphandrugdesignationmustberequestedbeforesubmittinganNDA. AfterFDA grantsorphandrug designation,theidentityofthedruganditspotentialorphanusearedisclosedpubliclybyFDA.Orphandrug designationdoesnotconveyanyadvantagein,orshortenthedurationof,theregulatoryreviewandapproval process.

ThefirstNDAapplicanttoreceiveFDA approvalforaparticularactivemoietytotreatararediseasefor whichithassuchdesignationisentitledtoaseven-yearexclusivemarketingperiodintheU.S. forthatproduct, forthatindication.Duringtheseven-yearexclusivityperiod,FDA maynotapproveanyotherapplicationsto marketthesamedrugforthesamedisease,exceptinlimitedcircumstances,suchas a showing of clinical superioritytotheproductwith orphandrug exclusivityby meansof greatereffectiveness,greatersafety,or providingamajorcontributiontopatientcare,orininstancesofdrugsupplyissues.Orphandrugexclusivity doesnotpreventFDA fromapprovingadifferentdrugforthesamediseaseor condition,or thesamedrug fora differentdiseaseorcondition.Otherbenefitsoforphandrug designationincludetaxcreditsforcertainresearch and an exemptionfromtheNDAuserfee.

PediatricInformation

UnderthePediatricResearchEquityAct,orPREA,NDAsorsupplementstoNDAs mustcontaindatato assessthesafetyand effectivenessof thedrug fortheclaimedindicationsin allrelevantpediatricsubpopulations andtosupport dosing andadministration foreachpediatric subpopulation forwhichthedrugissafeand effective.FDAmaygrantfullorpartialwaivers,ordeferrals,forsubmissionofdata.Unlessotherwiserequired byregulation,PREA does not applyto any drug foran indicationforwhich orphandesignationhas been granted exceptthatPREAwillapplytoanoriginalNDA foranewactiveingredientthatisorphan-designatedifthedrug isamolecularlytargetedcancerproductintendedforthetreatmentofanadultcancerandisdirectedata moleculartargetthatFDA determinestobesubstantiallyrelevanttothegrowthorprogressionofapediatric cancer.

TheBestPharmaceuticalsforChildrenAct,orBPCA, providesNDA holdersasix-monthextensionofany exclusivity—patentor nonpatent—fora drug ifcertainconditionsare met. Conditions for exclusivityinclude FDA’sdeterminationthatinformationrelatingtotheuse of a new drug in thepediatricpopulationmayproduce healthbenefitsinthatpopulation,FDA makingawrittenrequestforpediatricstudies,and theapplicantagreeing toperform,andreportingon, therequestedstudieswithinthestatutorytimeframe.ApplicationsundertheBPCA aretreatedas priorityapplications,with allof thebenefitsthatdesignationconfers.

Post-ApprovalRequirements

OnceanNDAisapproved,aproductwillbesubjecttocertainpost-approvalrequirements.Forinstance, FDA closelyregulatesthepost-approvalmarketingandpromotionofdrugs,includingstandardsand regulations fordirect-to-consumeradvertising,off-labelpromotion,industry-sponsoredscientificandeducationalactivities andpromotionalactivitiesinvolvingtheinternet.Drugsmaybemarketedonlyfortheapprovedindicationsand in a mannerconsistentwith theapprovedlabeling.

AdverseeventreportingandsubmissionofperiodicreportsarerequiredfollowingFDAapprovalofan NDA.FDAalsomayrequirepost-marketingtesting,knownasPhase4testing,riskevaluationandmitigation strategies, or REMS, and surveillance to monitor the effects of an approved product, or FDA may place conditionsonanapprovalthatcouldrestrictthedistributionoruseoftheproduct.Inaddition,qualitycontrol, drugmanufacture,packagingandlabelingproceduresmustcontinuetoconformto cGMPs afterapproval.Drug manufacturersandcertainoftheirsubcontractorsarerequiredtoregistertheirestablishmentswithFDA and certainstateagencies.RegistrationwithFDA subjectsentitiesto

periodicunannouncedinspectionsby FDA, duringwhichtheAgency inspectsmanufacturingfacilitiesto assesscompliancewith cGMPs. Accordingly, manufacturersmustcontinuetoexpendtime,moneyandeffortintheareasof productionand quality-controlto maintaincompliancewith cGMPs. Regulatoryauthoritiesmaywithdrawproductapprovalsor requestproduct recallsifa companyfailsto complywith regulatorystandards,if it encountersproblemsfollowing initial marketing,or ifpreviouslyunrecognizedproblemsaresubsequentlydiscovered.

The Hatch-WaxmanAmendments

Orange Book Listing

UndertheDrugPriceCompetitionandPatentTermRestorationActof1984,commonlyreferredto as the HatchWaxmanAmendments,NDAapplicantsarerequiredtoidentifytoFDAeachpatentwhoseclaimscover theapplicant’sdrugorapprovedmethodofusingthedrug.Uponapprovalofadrug,theapplicantmustupdate itslistingofpatentstotheNDA intimelyfashionandeachofthepatentslistedintheapplicationforthedrugis thenpublishedin theFDA’s Approved Drug Productswith TherapeuticEquivalenceEvaluations,commonly known as theOrange Book.

DrugslistedintheOrangeBookcan,inturn,becitedbypotentialgenericcompetitorsinsupportof approvalofanabbreviatednewdrugapplication,orANDA. AnANDA providesformarketingofadrugproduct thathasthesameactiveingredient(s),strength,routeofadministration,anddosageformasthelisteddrugand hasbeenshownthroughbioequivalencetestingtobetherapeuticallyequivalentto thelisteddrug. An approved ANDA productisconsideredtobetherapeuticallyequivalenttothelisteddrug.Otherthantherequirementfor bioequivalencetesting,ANDA applicantsarenotrequiredtoconduct,orsubmitresultsof,pre-clinicalorclinical teststoprovethesafetyoreffectivenessoftheirdrugproduct.DrugsapprovedundertheANDApathwayare commonlyreferredtoas“genericequivalents”tothelisteddrugandcanoftenbesubstitutedbypharmacists underprescriptionswrittenfortheoriginallisteddrug pursuantto eachstate’slaws on drug substitution.

TheANDA applicantisrequiredtocertifytotheFDA concerninganypatentsidentifiedforthereference listeddrugintheOrangeBook.Specifically,theapplicantmustcertifytoeachpatentinoneofthefollowing ways:(i)therequiredpatentinformationhasnot been filed;(ii)thelistedpatenthas expired;(iii)thelistedpatent hasnotexpiredbutwillexpireonaparticulardateandapprovalissoughtafterpatentexpiration;or (iv)thelisted patentisinvalidorwillnotbeinfringedbythenewproduct.A certificationthatthenew productwillnot infringe thealreadyapprovedproduct’slistedpatents,or thatsuch patentsareinvalid,iscalleda ParagraphIV certification.Forpatentslistedthatclaimanapprovedmethodofuse,undercertaincircumstancestheANDA applicantmayalsoelecttosubmitasectionviiistatementcertifyingthatitsproposedANDA labeldoesnot contain(orcarvesout)anylanguageregardingthepatentedmethod-of-useratherthancertifyto a listedmethod- of-usepatent.IftheapplicantdoesnotchallengethelistedpatentsthroughaParagraphIVcertification,the ANDAapplicationwillnotbeapproveduntilallthelistedpatentsclaimingthereferencedproducthaveexpired. IftheANDA applicanthasprovidedaParagraphIVcertificationtotheFDA,theapplicantmustalsosendnotice oftheParagraphIVcertificationtotheNDA-holderandpatentee(s)oncetheANDA hasbeenacceptedforfiling bytheFDA (referredtoasthe“noticeletter”).TheNDA andpatentholdersmaytheninitiatea patent infringementlawsuitinresponsetothenoticeletter.The filingof a patentinfringementlawsuitwithin45 days of thereceiptofaParagraphIVcertificationautomaticallypreventstheFDAfromapprovingtheANDA untilthe earlierof30monthsfromthedatethenoticeletterisreceived,expirationof thepatent,thedateof a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certificationisinvalidor not infringed,or a decisionin thepatentcasethatisfavorableto theANDAapplicant.

TheANDA applicationalsowillnotbeapproveduntilanyapplicablenon-patentexclusivitylistedinthe OrangeBookforthereferencedproducthasexpired.Insomeinstances,anANDAapplicantmayreceive approvalpriortoexpirationofcertainnon-patentexclusivityiftheapplicantseeks,andFDApermits,the omissionof such exclusivity-protectedinformationfromtheANDAprescribinginformation.

Exclusivity

UponNDA approvalofanewchemicalentity,orNCE, whichisadrugthatcontainsnoactivemoietythat hasbeenapprovedbyFDAinanyotherNDA,thatdrugreceivesfiveyearsofmarketingexclusivityduring whichFDAcannotreceiveanyANDA seekingapprovalofagenericversionofthatdrugunlesstheapplication containsaParagraphIVcertification,inwhichcasetheapplicationmaybe submittedone yearpriorto expiration oftheNCEexclusivity.Ifthere

isnolistedpatentintheOrangeBook,theremaynotbeaParagraphIVcertification,and,thus,noANDAforagenericversionofthedrugmaybefiledbeforetheexpirationofthe exclusivityperiod.

Certainchangestoanapproveddrug,suchastheapprovalof a new indication,theapprovalof a new strength,andtheapprovalof a new conditionof use, areassociatedwith a three-yearperiodof exclusivityfrom thedateofapprovalduringwhichFDAcannotapproveanANDA foragenericdrugthatincludesthechange.In someinstances,anANDA applicantmayreceiveapprovalpriortoexpirationofthethree-yearexclusivityifthe applicantseeks,andFDA permits,theomissionofsuchexclusivity-protectedinformationfromtheANDA packageinsert.

PatentTerm Extension

TheHatchWaxmanAmendmentspermitapatenttermextensionascompensationforpatenttermlost duringtheFDAregulatoryreviewprocess.Patenttermextension,however,cannotextendtheremainingtermof apatentbeyondatotalof14yearsfromtheproduct’sapprovaldate.AfterNDAapproval,ownersofrelevant drugpatentsmayapplyfortheextension.The allowablepatenttermextensioniscalculatedas halfof thedrug’s testingphase(thetimebetweenINDapplicationandNDA submission)and allof thereviewphase(thetime betweenNDA submissionandapproval)upto a maximumof fiveyears.The timecan be reducedforany time FDAdeterminesthattheapplicantdid not pursueapprovalwith due diligence.

TheUnitedStatesPatentandTrademarkOffice,orUSPTO, inconsultationwiththeFDA, reviewsand approvestheapplicationforanypatenttermextensionorrestoration.However,theUSPTOmaynotgrantan extensionbecauseof, forexample,failingto exercisedue diligenceduringthetestingphaseor regulatoryreview process,failingtoapplywithinapplicabledeadlines,failingtoapplypriortoexpirationofrelevantpatentsor otherwisefailingtosatisfyapplicablerequirements.Moreover,theapplicabletimeperiodorthescopeof patent protectionaffordedcouldbe lessthanrequested.

Thetotalpatenttermaftertheextensionmaynot exceed14 years,and only one patentcan be extended.The applicationfortheextensionmustbesubmittedpriorto theexpirationof thepatent,and forpatentsthatmight expireduringtheapplicationphase,thepatentownermayrequestan interimpatentextension.An interimpatent extensionincreasesthepatenttermbyoneyearandmaybereneweduptofourtimes.For eachinterimpatent extensiongranted,thepost-approvalpatentextensionisreducedbyoneyear.ThedirectoroftheUSPTO must determinethatapprovalofthedrug coveredby thepatentforwhich a patentextensionisbeingsoughtislikely. Interimpatentextensionsarenot availablefora drug forwhich an NDAhas not been submitted.

FDARegulationof Companion Diagnostics

Ifuseofaninvitrodiagnosticisessentialtosafeandeffectiveuseofadrugproduct,thentheFDA generallywillrequireapprovalorclearanceofthediagnostic,knownas a companiondiagnostic,atthesametime thattheFDA approvesthedrugproduct.FDA hasgenerallyrequiredinvitrocompaniondiagnosticsintendedto selectthepatientswhowillrespondtocancertreatmentto obtaina pre-marketapproval,or PMA, forthat diagnosticsimultaneouslywithapprovalof thedrug. The reviewof thesein vitrocompaniondiagnosticsin conjunctionwiththereviewofacancertherapeuticinvolvescoordinationofreviewbytheFDA’sCenterfor Drug Evaluationand Researchand by theFDA’s CenterforDevicesand RadiologicalHealth.Approvaland clearanceofacompaniondiagnosticalsorequiresahighlevelofcoordinationbetweenthedrugmanufacturer and devicemanufacturer,ifdifferentcompanies.

The PMA process,includingthegatheringof clinicaland preclinicaldataand thesubmissionto and review bytheFDA, cantakeseveralyearsorlonger.Itinvolvesarigorouspremarketreviewduringwhich theapplicant mustprepareandprovidetheFDA withreasonableassuranceofthedevice’ssafetyand effectivenessand informationaboutthedeviceanditscomponentsregarding,amongotherthings,devicedesign,manufacturing andlabeling.PMAapplicationsaresubjecttoasubstantialapplicationfee,whichistypicallyincreasedannually.

Inaddition,PMAsmustgenerallyincludetheresultsfromextensivepreclinicaland adequateand well-controlled clinicaltrialstoestablishthesafetyandeffectivenessofthedeviceforeachindicationforwhich FDAapprovalis sought.Inparticular,fora diagnostic,theapplicantmustdemonstratethatthediagnostichas adequatesensitivity and specificity,has adequatespecimenand reagentstability,and producesreproducibleresultswhen thesame sampleistestedmultipletimesby multipleusersatmultiplelaboratories.As partof thePMA review,theFDA willtypicallyinspectthemanufacturer’s

facilitiesforcompliancewith theQualitySystemRegulation,or QSR, which imposeselaboratetesting,control,documentationand otherqualityassurancerequirements.

PMAapprovalisnotguaranteed,andtheFDAmayultimatelyrespondtoaPMAsubmissionwithanot approvabledeterminationbasedondeficienciesintheapplicationandrequireadditionalclinicaltrialorother datathatmaybe expensiveand time-consumingto generateand thatcan substantiallydelay approval. If the FDA’sevaluationofthePMAapplicationisfavorable,theFDAtypicallyissuesanapprovableletterrequiring theapplicant’sagreementtospecificconditions,such as changesin labeling,or specificadditionalinformation, suchassubmissionoffinallabeling,inordertosecurefinalapprovalofthePMA.IftheFDA concludesthatthe applicablecriteriahavebeenmet,theFDA willissueaPMAfortheapprovedindications,which can be more limitedthanthoseoriginallysoughtbytheapplicant.ThePMAcanincludepost-approvalconditionsthatthe FDA believesnecessarytoensurethesafetyandeffectivenessofthedevice,including,amongotherthings, restrictionson labeling,promotion,saleand distribution.

Afteradeviceisplacedonthemarket,itremainssubjecttosignificantregulatoryrequirements.Medical devicesmaybemarketedonlyfortheusesand indicationsforwhich theyareclearedor approved.Device manufacturers must also register their establishment(s), including payment of an annual establishment registrationfee,andlisttheirdevice(s)withtheFDA. Amedicaldevicemanufacturer’smanufacturingprocesses andthoseofitssuppliersarerequiredtocomplywiththeapplicableportionsoftheQSR,whichcoverthe methodsanddocumentationofthedesign,testing,production,processes,controls,qualityassurance,labeling, packagingand shippingof medicaldevices.Domesticfacilityrecordsand manufacturingprocessesaresubjectto periodicunscheduledinspectionsbytheFDA.TheFDAalsomayinspectforeignfacilitiesthatexportproducts to theUnitedStates.

Other HealthcareLaws

InadditiontoFDArestrictionsonmarketingofpharmaceuticalproducts,severalothertypesofstateand federallawshavebeenappliedtorestrictcertaingeneralbusinessand marketingpracticesin thepharmaceutical industry.Theselawsincludeanti-kickback,falseclaims,transparencyand healthinformationprivacylaws and otherhealthcarelaws and regulations.

The federalAnti-KickbackStatuteprohibits,amongotherthings,knowingly and willfullyoffering,paying, solicitingorreceivingremunerationtoinduce,orinreturnfor,purchasing,leasing,orderingor arrangingforthe purchase,leaseororderofanyhealthcareitemorservicereimbursableunderMedicare,Medicaid,or other federallyfinancedhealthcareprograms.ThePatientProtectionandAffordableCareActasamendedbythe HealthCareandEducationReconciliationAct,collectively,theACA, amendedtheintentelementof thefederal statutesothatapersonorentitynolongerneedstohaveactualknowledgeofthestatuteorspecificintentto violateitinorderto commita violation.This statutehas been interpretedto applyto arrangementsbetween pharmaceuticalmanufacturersontheonehandandprescribers,purchasersandformularymanagers,among others,ontheother.Although therearea numberof statutoryexceptionsand regulatorysafeharborsprotecting certaincommonactivitiesfromprosecutionor otherregulatorysanctions,theexceptionsand safeharborsare drawnnarrowly,and practicesthatinvolveremunerationintendedto induceprescribing,purchasesor recommendationsmaybe subjectto scrutinyiftheydo not qualifyforan exceptionor safeharbor.Additionally, theACA amendedthefederalAnti-KickbackStatutesuch thata violationof thatstatutecan serveas a basisfor liabilityunderthefederalcivilFalseClaimsAct.

Federalcivilandcriminalfalseclaimslaws,includingthefederalcivilFalseClaimsAct,prohibitanyperson or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government,orknowinglymaking,orcausingtobemade,afalsestatementtohaveafalseclaimpaid.Thisincludes claimsmadetoprogramswherethefederalgovernmentreimburses,suchasMedicareandMedicaid,aswell as programswherethefederalgovernmentisadirectpurchaser,suchaswhenitpurchasesoff the Federal Supply Schedule.Pharmaceuticalandotherhealthcarecompanieshavebeenprosecutedunderthese laws for, among other things,allegedlyinflatingdrugpricestheyreporttopricingservices,whichinturnwereusedbythegovernment to setMedicareandMedicaidreimbursementrates,andfor allegedly providing free product to customers with the expectationthatthecustomerswouldbillfederalprogramsfortheproduct. In addition, certain marketing practices, includingoff-labelpromotion,mayalsoviolatefalseclaimslaws.Moststatesalso have statutes or regulations similartothefederalAnti-KickbackStatuteandcivilFalseClaimsAct,whichapplytoitemsand services reimbursedunderMedicaidandotherstateprograms,or,inseveralstates,applyregardlessofthepayor.

Otherfederalstatutespertainingto healthcarefraudand abuseincludethecivilmonetarypenaltiesstatute, which prohibits,amongotherthings,theofferor paymentof remunerationto a Medicaidor Medicarebeneficiary thattheofferororpayorknowsorshouldknowislikelytoinfluencethebeneficiaryto ordera receivea reimbursableitemor servicefroma particularsupplier,and theadditionalfederalcriminalstatutescreatedby the HealthInsurancePortabilityandAccountabilityActof1996,orHIPAA, whichprohibits,amongotherthings, knowinglyandwillfullyexecutingorattemptingtoexecuteaschemetodefraudanyhealthcarebenefitprogram orobtainbymeansoffalseor fraudulentpretenses,representationsor promisesany moneyor propertyowned by orunderthecontrolof any healthcarebenefitprogramin connectionwith thedeliveryof or paymentfor healthcarebenefits,itemsor services.

Inaddition,HIPAA, as amendedby theHealthInformationTechnologyforEconomicand ClinicalHealth Actof2009,orHITECH, andtheirrespectiveimplementingregulations,includingtheFinalOmnibusRule publishedonJanuary25,2013,imposeobligationsoncertainhealthcareproviders,healthplans,and healthcare clearinghouses,knownascoveredentities,as wellas theirbusinessassociatesand theirsubcontractorsthat performcertainservicesinvolvingthestorage,use or disclosureof individuallyidentifiablehealth information, includingmandatorycontractualterms,withrespecttosafeguardingtheprivacy,security,andtransmissionof individuallyidentifiablehealthinformation,andrequirenotificationto affectedindividualsand regulatory authoritiesofcertainbreachesofsecurityofindividuallyidentifiablehealthinformation.HITECH increasedthe civilandcriminalpenaltiesthatmaybeimposedagainstcoveredentities,businessassociatesand possiblyother persons,and gave stateattorneysgeneralnew authorityto filecivilactionsfordamagesor injunctionsin federal courtstoenforcethefederalHIPAAlawsandseekattorney’sfeesandcostsassociatedwithpursuingfederal civilactions.Inaddition,manystatelaws governtheprivacyand securityof healthinformationin certain circumstances,manyofwhich differfromeachotherin significantways and maynot have thesameeffect,and oftenarenot pre-emptedby HIPAA.

Further,pursuanttotheACA,theCentersforMedicare&MedicaidServices,orCMS,hasissuedafinal rulethatrequirescertainmanufacturersofprescriptiondrugsto collectand annuallyreportinformationon certain paymentsortransfersofvalueto physicians,as definedby such law, and teachinghospitals,as wellas ownership and investmentinterestsheldby physiciansand theirimmediatefamilymembers.The reporteddata is made availableinsearchableformonapublicwebsiteonanannualbasis.Failureto submitrequiredinformationmay resultin civilmonetarypenalties. Beginning calendar year 2021, manufacturers must collect information regarding payments and other transfersof valueto physicianassistants,nurse practitioners, clinicalnursespecialists,certifiedregisterednurseanesthetists,anesthesiologistassistantsand certifiednurse- midwives for reporting in 2022. The reported information is made publicly available on a searchable website.

We mayalsobe subjectto analogousstateand foreignanti-kickbackand falseclaimslaws thatmay apply to salesor marketingarrangementsand claimsinvolvinghealthcareitemsor servicesreimbursedby non- governmentalthirdpartypayors,includingprivateinsurers,orthatapplyregardlessof payor.In addition,several states now require prescription drug companies to report certain expenses relating to the marketing and promotionof drug productsand to reportgiftsand paymentsto individualhealthcarepractitionersin these states. Otherstatesprohibitvariousmarketing-relatedactivities,suchastheprovisionofcertainkindsofgiftsormeals.

Stillotherstatesrequirethepostingofinformationrelatingtoclinicalstudiesand theiroutcomes.Some states requirethereportingofcertaindrugpricinginformation,includinginformationpertainingto and justifyingprice increases.In addition,certainstatesrequirepharmaceuticalcompaniesto implementcomplianceprogramsand/or marketingcodes.Severaladditionalstatesareconsideringsimilarproposals.Certainstatesand localjurisdictions alsorequiretheregistrationofpharmaceuticalsalesrepresentatives.Compliancewith theselaws isdifficultand timeconsuming,andcompaniesthatdo not complywith thesestatelaws facecivilpenalties.Additionally,we mayalsobe subjectto stateand foreignlaws governingtheprivacyand securityof healthinformationin some circumstances,manyofwhichdifferfromeachotherinsignificantwaysandoftenarenot preemptedby HIPAA, thuscomplicatingcomplianceefforts.

Effortstoensurethatbusinessarrangementswiththirdpartiescomplywithapplicablehealthcarelaws and regulationsinvolvesubstantialcosts.Ifadrugcompany’soperationsarefoundtobeinviolationofanysuch requirements,itmaybesubjecttosignificantpenalties,includingcivil,criminaland administrativepenalties, damages,fines,disgorgement,imprisonment,thecurtailmentorrestructuringofitsoperations,lossofeligibility toobtainapprovalsfromtheFDA, exclusionfromparticipationingovernmentcontracting,healthcare reimbursementorotherfederalor stategovernmenthealthcareprograms,includingMedicareand Medicaid, integrity oversight and reporting obligations, imprisonment, and reputational harm. Although effective complianceprogramscanmitigatetheriskofinvestigationandprosecutionfor

violationsoftheselaws,these riskscannotbeentirelyeliminated.Anyactionforan allegedor suspectedviolationcan causea drug companyto incursignificantlegalexpensesanddivertmanagement’sattentionfromtheoperationofthebusiness,evenif such actionissuccessfullydefended.

U.S.HealthcareReform

IntheUnitedStatestherehavebeen, and continueto be, proposalsby thefederalgovernment,state governments,regulatorsandthird-partypayorstocontrolormanagetheincreasedcostsofhealthcareand, more generally,toreformtheU.S. healthcaresystem.Thepharmaceuticalindustryhasbeenaparticularfocusofthese effortsandhasbeensignificantlyaffectedbymajorlegislativeinitiativesForexample,inMarch2010, theACA wasenacted,whichintendedtobroadenaccesstohealthinsurance,reduceor constrainthegrowth of healthcare spending,enhanceremediesagainstfraudand abuse,add new transparencyrequirementsforthehealthcareand healthinsuranceindustries,imposenewtaxesandfeesonthehealthindustryand imposeadditionalhealthpolicy reforms,substantiallychangedthewayhealthcareisfinancedbybothgovernmentaland privateinsurers,and significantlyimpactstheU.S. pharmaceuticalindustry.TheACA, amongotherthings,(i)subjectedtherapeutic biologicstopotentialcompetitionby lower-costbiosimilarsby creatinga licensureframeworkforfollow-on biologic products, (ii) proscribed a new methodology by which rebates owed by manufacturers under the MedicaidDrug RebateProgramarecalculatedfordrugsand therapeuticbiologicsthat are inhaled, infused, instilled,implantedorinjected,(iii)increasedtheminimumMedicaidrebatesowedby manufacturersunderthe MedicaidDrugRebateProgramand extendedtherebateprogramto individualsenrolledin Medicaidmanaged careorganizations,(iv)establishedannualnondeductiblefeesandtaxesonmanufacturersof certainbranded prescriptiondrugsandtherapeuticbiologics,apportionedamongtheseentitiesaccordingto theirmarketsharein certaingovernmenthealthcareprograms(v)establishedanewMedicarePartDcoveragegapdiscountprogram, inwhichmanufacturersmustagreeto offer50% (now 70%)pointof-salediscountsoffnegotiatedpricesof applicablebranddrugsand therapeuticbiologicsto eligiblebeneficiariesduringtheircoveragegap period,as a conditionforthemanufacturer’soutpatientdrugsand therapeuticbiologicsto be coveredunderMedicarePartD, (vi)expandedeligibilitycriteriaforMedicaidprogramsby, amongotherthings,allowingstatesto offerMedicaid coveragetoadditionalindividualsandbyaddingnewmandatoryeligibilitycategoriesforindividualswith incomeator below 133% of thefederalpoverty level, thereby potentiallyincreasingmanufacturers’Medicaid rebate liability,(vii)expanded the entitieseligiblefor discounts under the Public Health program (viii)createda newPatient-CenteredOutcomesResearchInstituteto oversee,identifyprioritiesin, and conductcomparative clinicaleffectivenessresearch,alongwithfundingforsuch research,and (ix)establisheda CenterforMedicare andMedicaidInnovationatCMSto testinnovativepaymentand servicedeliverymodelsto lowerMedicareand Medicaidspending,potentiallyincludingprescriptiondrug spending.

There have been legislative and judicial efforts tomodify,repeal, orotherwiseinvalidateall,orcertainprovisionsof,theACA, including measures taken during the Trump administration. TheTaxCuts and Jobs Act of 2017, or the Tax Reform Act, among otherthings,includeda provisionthatrepealed,effectiveJanuary1, 2019, thetax-basedshared responsibility paymentimposedbytheACAoncertainindividualswhofailtomaintainqualifyinghealthcoverageforallor partof a yearthatiscommonlyreferredto as the“individualmandate.” In November 2020, the United States Supreme Court held oral arguments on the U.S. Court of Appeals for the Fifth Circuit’s decision that held that the individual mandate is unconstitutional. It is uncertain how the United States Supreme court will rule on this case or how healthcare measures of the Biden administration will impact the ACA and our business. Additionally,the2020 federalspending packagepermanentlyeliminated,effectiveJanuary1,2020,theACA-mandated“Cadillac”taxon high-cost employer-sponsoredhealthcoverageand medicaldevicetaxand, effectiveJanuary1, 2021, also eliminatesthe healthinsurertax.Further,theBipartisanBudgetActof2018,ortheBBA,amongotherthings,amendedthe ACA, effectiveJanuary1,2019,toincreasefrom50%to70%thepoint-of-salediscountthatisowed by pharmaceuticalmanufacturerswho participatein Medicare PartD and to closethe coveragegap in most Medicaredrugplans, commonlyreferredtoasthe“donuthole.”In addition, CMS published a final rule that would give states greater flexibility, effective January 1, 2020, in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces. Wecannotpredicttheultimatecontent,timingoreffectofanyhealthcare reformlegislationor theimpactof potentiallegislationon us.

Otherlegislativechangeshavebeenproposedand adoptedin theUnitedStatessincetheACA was enactedto reducehealthcareexpenditures.UnitedStatesfederalgovernmentagenciesalsocurrentlyface potentiallysignificantspendingreductions,whichmayfurtherimpacthealthcareexpenditures.OnAugust2, 2011,the Budget Control Act of 2011 among other things, created measures for spending reductions by Congress.AJointSelectCommitteeonDeficitReduction,

taskedwithrecommendingatargeteddeficitreduction ofatleast$1.2trillionfortheyears2013 through2021, was unableto reachrequiredgoals,therebytriggeringthe legislation’sautomaticreductiontoseveralgovernmentprograms.This includes aggregatereductionsof Medicarepaymentstoprovidersof2%perfiscalyear.ThesereductionswentintoeffectonApril1,2013and, duetosubsequentlegislativeamendmentstothestatute,includingtheBBA, willremainin effectthrough2030 unlessadditionalCongressionalactionistaken.TheCARESAct,whichwassignedintolawinMarch2020and isdesignedtoprovidefinancialsupportandresourcestoindividualsand businessesaffectedby theCOVID-19 pandemic,suspendedthe2%MedicaresequesterfromMay1,2020throughDecember31,2020,andextended thesequesterbyoneyear,through2030. The Consolidated Appropriations Act, 2021 extended the suspension of the 2% Medicare sequester through March 31, 2021. Moreover,onJanuary2,2013,theAmericanTaxpayerReliefActof2012wassignedintolaw,which,amongotherthings,furtherreducedMedicarepaymentstoseveraltypesof providers,includinghospitals,imagingcentersandcancertreatmentcenters,and increasedthestatuteof limitationsperiodforthegovernmenttorecoveroverpaymentsto providersfromthreeto fiveyears.Iffederal spendingisfurtherreduced,anticipatedbudgetaryshortfallsmayalsoimpacttheabilityofrelevantagencies, suchastheFDAortheNationalInstitutesofHealthtocontinuetofunctionatcurrentlevels.Amountsallocated to federalgrantsand contractsmaybe reducedor eliminated.These reductionsmayalso impactthe abilityof relevantagenciesto timelyreviewand approveresearchand development,manufacturing,and marketing activities,which maydelayour abilityto develop,marketand sellany productswe maydevelop.

Recently,therehas been heightenedgovernmentalscrutinyoverthemannerin which manufacturersset pricesfortheirmarketedproducts,whichhasresultedinseveralCongressionalinquiriesandproposedand enactedfederalandstatelegislationdesignedto, amongotherthings,bringmoretransparencyto productpricing, reviewtherelationshipbetweenpricingandmanufacturerpatientprograms,and reformgovernmentprogram reimbursement methodologies for drug products. At the federal level, the Trump administration’s budget proposalforfiscalyear2021includeda$135 billionallowanceto supportlegislativeproposalsseekingto reduce drugprices,increasecompetition,lowerout-of-pocketdrugcostsforpatients,andincreasepatientaccessto lower-costgenericand biosimilardrugs.

In particular, July24,2020and September13, 2020, theTrump administrationannouncedseveralexecutiveordersrelatedto prescriptiondrugpricingthatseektoimplementseveraloftheadministration’sproposals.As a result,theFDA alsoreleasedafinalruleon September24, 2020 providingguidanceforstatesto buildand submitimportation plansfordrugsfromCanada. The Trump and Biden administrations both issued executive orders intended to favor government procurement from domestic manufacturers. In addition, the Trump administration issued an executive order specifically aimed at the procurement of pharmaceutical products, which instructed the federal government to develop a list of “essential” medicines and then buy those and other medical supplies that are manufactured, including the manufacture of the API, in the United States. It is unclear whether this executive order or something similar will be implemented by the Biden Administration.

Further,onNovember20,2020,HHS finalizedaregulationremovingsafeharbor protectionforpricereductionsfrompharmaceuticalmanufacturerstoplansponsorsunderPartD,eitherdirectly orthroughpharmacybenefitmanagers,unlessthepricereductionisrequiredby law. The rulealsocreatesa new safeharborforpricereductionsreflectedatthepoint-of-sale,as wellas a safeharborforcertainfixedfee arrangementsbetweenpharmacybenefitmanagersandmanufacturers.CMS alsopublishedaninterimfinalrule thatestablishesanMFNModelforMedicarePartBdrugpayment.Thisregulationwouldsubstantiallychange thedrugreimbursementlandscapeasitbasesMedicarePartB paymentfor50 selecteddrugson pricesin foreign countriesinsteadofASPandestablishesafixedadd-onpaymentinplaceofthecurrent6percent(4.3percent aftersequestration)ofASP. TheMFNdrugpaymentamountisexpectedtobelowerthanthecurrentASP-based limitbecauseU.S. drugpricesaregenerallythehighestin theworld. On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule, and itfacesuncertainprospectsforimplementation.

Atthestatelevel,legislaturesareincreasinglypassinglegislationand implementingregulationsdesignedto controlpharmaceuticaland biologicalproductpricing,includingpriceor patientreimbursementconstraints, discounts,restrictionsoncertainproductaccessandmarketingcostdisclosureand transparencymeasures,and, in mostcases,designedto encourageimportationfromothercountriesand bulk purchasing.

ItispossiblethatadditionalgovernmentalactionistakentoaddresstheCOVID-19 pandemic.Forexample, onApril18,2020,CMSannouncedthatqualifiedhealthplanissuersundertheACA maysuspendactivities relatedtothecollectionand reportingof qualitydatathatwould have otherwisebeen reportedbetweenMay and June 2020 giventhechallengeshealthcareprovidersarefacingrespondingto theCOVID-19virus.

Additionally,onMay30,2018,theTrickettWendler,FrankMongiello,JordanMcLinn,andMatthew Bellina Right to Try Act of 2017 was signed into law. The law, among other things, provides a federal frameworkforcertainpatientsto accesscertaininvestigationalnew drug productsthathave completeda Phase I clinicaltrialandthatareundergoinginvestigationforFDA approval.Undercertaincircumstances,eligible patientscanseektreatmentwithoutenrollinginclinicaltrialsandwithoutobtainingFDA authorizationunderan FDA expandedaccessprogram;however, manufacturersarenot obligatedto provideinvestigationalnew drug productsunderthecurrentfederalrightto trylaw.

Coverage and Reimbursement

PatientsintheUnitedStatesandelsewheregenerallyrelyonthird-partypayorstoreimbursepartorallof thecostsassociated withtheirprescription drugs.Accordingly,marketacceptanceofourdrugproductsis dependenton theextentto which third-partycoverageand reimbursementisavailablefrom governmenthealth administrationauthorities(includingin connectionwith governmenthealthcareprograms,such as Medicareand Medicaid in the United States), private healthcare insurers and other healthcare funding organizations. Significantuncertaintyexistsastothecoverageandreimbursementstatusofanydrugproductsforwhichwe mayobtainregulatoryapproval.Coveragedecisionsmaynot favornew drug productswhen moreestablishedor lower-costtherapeuticalternativesarealreadyavailable.Patientsareunlikelyto use our productsunless reimbursementisadequateto coverallor a significantportionof thecostof our drug products.

Coverageandreimbursementpoliciesfordrugproductscandiffersignificantlyfrompayortopayor as there is nouniformpolicyofcoverageandreimbursementfordrugproductsamongthird-partypayorsinthe United States. Theremaybesignificant delays in obtaining coverage and reimbursement as the process of determining coverage andreimbursementisoftentime-consumingandcostly which will require us to provide scientific and clinical supportfortheuseofourproductstoeachpayor separately, with no assurance that coverage or adequate reimbursementwillbeobtained. It is difficult to predict at this time what government authorities and third-party payorswilldecidewithrespectto coverage and reimbursement for our drug products. Additionally, we may develop,eitherbyourselvesorwithcollaborators,companiondiagnostictestsforourproductcandidatesfor certain indications.We, or our collaborators, if any, will be required to obtain coverage and reimbursement for these tests separateandapartfromthecoverageandreimbursementweseekforourproductcandidates,onceapproved.

Themarketforourproductcandidateswilldepend significantlyon accessto third-partypayors’drug formularies orlists of medications for which third-party payors provide coverage and reimbursement. Competitiontobeincludedinsuchformulariesoftenleadstodownward pricingpressures.In particular,third- partypayorsmayrefuseto includea particularreferencelisteddrug in theirformulariesor otherwiserestrict patientaccessto a referencelisteddrug when a lesscostlygenericequivalentor otheralternativeisavailable.

TheU.S. government,statelegislaturesandforeigngovernmentalentitieshave shown significantinterestin implementingcostcontainmentprogramstolimitthegrowthofgovernment-paidhealthcarecosts,including pricecontrols,restrictionsonreimbursementandcoverageandrequirementsforsubstitutionof genericproducts forbrandedprescriptiondrugs.Adoption of governmentcontrolsand measures,and tighteningof restrictive policiesinjurisdictionswithexistingcontrolsand measures,couldexcludeor limitour drugsproductsfrom coverageand limitpaymentsforpharmaceuticals.

Inaddition,weexpectthattheincreasedemphasisonmanagedcareand costcontainmentmeasuresin the UnitedStatesbythird-partypayorsandgovernmentauthoritiesto continueand willplacepressureon pharmaceuticalpricingandcoverage.Coveragepoliciesand third-partyreimbursementratesmaychangeatany time.Eveniffavorablecoverageandreimbursementstatusisattainedforoneormoredrugproductsforwhich wereceiveregulatoryapproval,lessfavorablecoveragepoliciesand reimbursementratesmaybe implementedin thefuture.

Human Capital

Employees

AsofDecember 31, 2021,wehad116full-timeemployees.Womenrepresentapproximately45% of our employeeswithapproximately37%holdingseniormanagementlevel/leadershiproles. Oftheseemployees, 30 have an M.D. or a Ph.D. From time to time, wealso retain independent contractors to support our organization.None of our employeesarerepresentedby a laborunion or coveredby collectivebargaining agreements,and we believeour relationshipwith our employeesisgood.

Diversity& Inclusion

Wearecommittedto creatingand maintaininga workplacefreefromdiscriminationor harassmenton the basis of color, race, sex, national origin, ethnicity, religion, age, disability, sexual orientation, gender identification or expression or any other status protected by applicable law. Our management team and employeesareexpectedtoexhibitandpromotehonest,ethicalandrespectfulconductintheworkplace.Allof ouremployeesmustadhereto a code of conductthatsetsstandardsforappropriatebehaviorand arerequiredto attendannualtrainingtohelpprevent,identify,reportand stopany typeof discriminationand harassment.Our recruitment,hiring,development,training,compensation,and advancementatour companyis based on qualifications,performance,skillsand experiencewithoutregardto gender,raceand ethnicity.

CompetitivePay & Benefits

Westrivetoprovidepay,comprehensivebenefitsandservicesthathelpmeetthevaryingneedsof our employees.Our totalrewardspackageincludescompetitivepay;comprehensivehealthcarebenefitspackagefor employees,withfamilymemberhealthcarebenefitscoveredat80%;a healthsavingsaccountwith company contribution;20daysofpaidtimeoffandpaidholidays;familymedicalleaveandflexiblework schedules.In addition,weoffereveryfull-timeemployee,both exemptand non-exempt, thebenefitof equityownershipin the companythroughstockoptiongrantsandouremployeestockpurchaseplan.Wesponsora401(k)planthat includesa discretionarymatchingcontribution.

EmployeeDevelopment& Training

We focus onattracting, retaining, and cultivating talented individuals. We emphasize employee developmentandtrainingbyprovidingaccesstoawiderangeofonlineand instructorleddevelopmentand continuallearningprograms.Employeesareencouragedto attendscientific,clinicaland technologicalmeetings and conferencesand have accessto broadresourcestheyneed to be successful.

Safety

Thesafety,healthandwellnessofouremployeesisatoppriority.Inresponseto the COVID-19 pandemic, wehave implementedasafetyprotocolsincludingshiftworkschedulingto reducenumberof peoplein thefacility, requirementsforthewearingofmasksandforsocialdistancing,increasedcleaningproceduresand readily availablehandsanitizer.Theseprotocolsaredesignedto complywith healthand safetystandardsas requiredby federal,stateandlocalgovernmentagencies,takingintoconsiderationguidelinesof theCentersforDisease Controland Preventionand otherpublichealthauthorities.In addition,we have providedwork-at-home arrangementsforemployeeswho areableto do so.

Corporate Information

We were incorporated under the laws of the State of Delaware in February 2016. Our principal executive offices are located at 200 Powder Mill Road, Wilmington, DE 19803, and our telephone number is (302) 467-1280. Our website address is www.preludetx.com. The information contained on, or that can be accessed through, our website is not part of, and is not incorporated by reference into, this prospectus. Investors should not rely on any such information in deciding whether to purchase our common stock.

The mark “Prelude Therapeutics,” the Prelude logo and all product names are our common law trademarks. All other service marks, trademarks and trade names appearing in this Annual Report on Form 10-K are the property of their respective owners. Solely for convenience, the trademarks and tradenames referred to in this Annual Report on Form 10-K appear

without the ® and TM symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.

Available Information

We make available free of charge electronic versions of our Annual Report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports on our website, preludetx.com, as soon as reasonably practicable after we electronically file or furnish such materials to the Securities and Exchange Commission, or SEC. The reports are also available at www.sec.gov.

Item 1A. Risk Factors

RISK FACTORS

Investing in our common stock involves a high degree of risk. Before making your decision to invest in shares of our common stock, you should carefully consider the risks and uncertainties described below, together with the other information contained in this Annual Report on Form 10-K, including our financial statements and the related notes and “Management’s Discussion and Analysis of Financial Condition and Results of Operations”. The risks and uncertainties described below are not the only ones we face. Additional risks and uncertainties that we are unaware of, or that we currently believe are not material, may also become important factors that affect us. We cannot assure you that any of the events discussed below will not occur. These events could have a material and adverse impact on our business, financial condition, results of operations and prospects. If that were to happen, the trading price of our common stock could decline, and you could lose all or part of your investment.

Summary of Risk Factors

Our business is subject to several risks and uncertainties, including those immediately following this summary. Some of these risks are:

• Rights to improvements to our product candidates may be held by third parties.

Risks Relatedto Our FinancialPositionand Need forCapital

We have a limitedoperatinghistory,which maymakeitdifficultto evaluatethe successof our businessto dateand to assessour futureviability.We have incurredsignificantoperatinglossessinceour inception and have not generatedany revenue.We expectto incur continuedlossesforthe foreseeablefutureand mayneverachieveor maintainprofitability.

Investmentindrugdevelopmentisahighlyspeculativeundertakingandinvolvesasubstantialdegreeof risk.Wecommencedoperationsin2016and area clinical-stagebiopharmaceuticalcompanywith a limited operatinghistory.Wehave not yetcommercializedany product,and we do not expectto generaterevenuefrom salesofany productsforseveralyears,ifatall.Consequently,therehave been limitedoperationsupon which we oryoucanevaluateourbusiness. Predictionsaboutour futuresuccessor viabilitymaynot be as accurateas theycouldbeifwehada longeroperatinghistoryor a historyof successfullydevelopingand commercializing cancertherapies.FortheyearendedDecember 31, 2021,wereportedanetlossof$111.7million.AsofDecember 31, 2021,wehadanaccumulateddeficitof$219.1million.Weexpecttocontinue to incursignificantresearchand developmentand otherexpensesrelatedto our ongoing operations.

Sinceourinception,wehavefocusedsubstantiallyallofoureffortsandfinancialresourceson theresearch, preclinicalandclinicaldevelopmentofour productcandidates,PRT543,PRT811, PRT1419, and PRT2527,and our research effortsonotherpotentialproductcandidatestargetingPRMT5, MCL1,CDK9, andBRM, otherwiseknownasSMARCA2.As of December 31, 2021, our cash, cashequivalents, and marketable securitieswere $291.2 million.

Weexpecttoincurincreasinglevelsofoperatinglossesfortheforeseeablefuture,particularlyaswe advance PRT543, PRT811, PRT1419 and PRT2527 through clinical development. Our prior losses, combined with expectedfuturelosses,havehadandwillcontinueto have an adverseeffecton our stockholders’equityand workingcapital.Weexpectourresearchanddevelopmentexpensestosignificantlyincreasein connectionwith our additionalplannedclinicaltrialsforour leadproductcandidates,includingtheongoing Phase 1 clinicaltrials andtheplannedexpansioncohortsofPRT543 andPRT811, theongoingPhase1clinicaltrialfor oral PRT1419 and developmentandsubsequentINDsofotherfutureproductcandidateswemaychooseto pursue,including IV PRT1419, PRT2527,ourCDK9inhibitor,aSMARCA2 proteindegraderandakinaseinhibitor.Inaddition,ifweobtain marketingapprovalforPRT543,PRT811, PRT1419, PRT2527, oranotherproductcandidate,wewillincursignificantsales, marketing and outsourced manufacturing expenses in connection with the commercialization of PRT543, PRT811, PRT1419, PRT2527 orsuchotherproductcandidate,respectively.Wewillalsocontinuetoincuradditionalcosts associatedwith operatingas a publiccompany.As a result,we expectto continueto incursignificantand increasingoperatinglossesfortheforeseeablefuture.Becauseofthenumerousrisksand uncertaintiesassociated withdevelopingpharmaceuticalproducts,weareunabletopredicttheextentofanyfuturelossesorwhenwe willbecomeprofitable,ifatall.Evenifwedobecomeprofitable,wemaynotbeabletosustainorincreaseour profitabilityon a quarterlyor annualbasis.We expectour financialconditionand operatingresultsto fluctuate significantlyfromquarter-to-quarterand year-to-yeardue to a varietyof factors,manyof which arebeyond our control.Accordingly,youshouldnotrelyupon theresultsof any quarterlyor annualperiodsas indicationsof futureoperatingperformance.

Ourabilitytobecomeprofitabledependsupon our abilityto generaterevenue.To date,we have not generatedanyrevenueand we do not know when, or if,we willgenerateany revenue.We do not expectto generatesignificantrevenueunlessand untilwe obtainmarketingapprovalfor,and beginto sell,PRT543, PRT811, PRT1419, PRT2527, oranotherproductcandidate.Ourabilitytogeneraterevenuedependson a numberof factors, including,but not limitedto, our abilityto:

• obtain, maintain, protect and defend our intellectual property portfolio; and

To become and remain profitable, we must succeed in designing, developing, and eventually commercializingproductsthatgeneratesignificantrevenue.Thiswillrequireustobesuccessfulinarangeof challengingactivities,includingcompletingpreclinicaltestingandclinicaltrialsforour productcandidates, designingadditionalproductcandidates,establishingarrangementswith third partiesfor the manufactureof clinicalsuppliesofourproductcandidates,obtainingmarketingapprovalforour productcandidatesand manufacturing,marketingandsellingany productsforwhich we mayobtainmarketingapproval.We areonly in thepreliminarystagesofmostof theseactivities.We mayneversucceedin theseactivitiesand, even ifwe do, maynevergeneraterevenuesthataresignificantenough to achieveprofitability.

Incaseswherewearesuccessfulinobtainingregulatoryapprovaltomarketoneormoreofourproduct candidates,ourrevenuewillbedependent,inpart,uponthesizeofthemarketsintheterritoriesforwhichwe gainregulatoryapproval,theacceptedpricefortheproduct,theabilitytoobtaincoverageandreimbursement, andwhetherweownthecommercialrightsforthatterritory.Ifthenumberofouraddressablepatientsisnot as significantasweestimate,theindicationapprovedbyregulatoryauthoritiesisnarrowerthanweexpect,or the treatmentpopulationisnarrowedbycompetition,physicianchoiceor treatmentguidelines,we maynot generate significantrevenuefromsalesof such products,even ifapproved.

Becauseofthenumerousrisksanduncertaintiesassociatedwithpharmaceuticalproductdevelopment,we areunabletoaccuratelypredictthetimingoramountof increasedexpenseswe willincuror when, or if,we will beabletoachieveprofitability.IfwedecidetoorarerequiredbytheFDA orregulatoryauthoritiesinother jurisdictionstoperformstudiesor clinicaltrialsin additionto thosecurrentlyexpected,or ifthereareany delays inestablishingappropriatemanufacturingarrangementsfor,ininitiatingor completingour currentand planned clinicaltrialsfor,or in thedevelopmentof, any of our productcandidates,our expensescouldincreasematerially and profitabilitycouldbe furtherdelayed.

Evenifwedoachieveprofitability,wemaynotbeabletosustainorincreaseprofitabilityon a quarterlyor annualbasis.Ourfailuretobecomeand remainprofitablewould depressthevalueof our companyand could impairourabilitytoraisecapital,expand our business,maintainour researchand developmentefforts,diversify ourproductofferingsorevencontinueouroperations.Adeclineinthevalueofourcompanycouldalsocause you to loseallor partof your investment.

We willrequiresubstantialadditionalfunding to pursue our business objectives.Ifwe are unable to raisecapitalwhenneeded or on termsacceptableto us, we could be forced to delay,reduceor eliminateour researchor drug developmentprograms,any futurecommercialization effortsor otheroperations.

Weexpectourexpensestoincreasesubstantiallyinconnectionwithourongoingactivities,particularlyas weadvanceourproductcandidates,PRT543,PRT811,PRT1419 and PRT2527, andotherpipelineproductcandidates throughclinicaldevelopment,and seekto designadditionalproductcandidatesfromour discoveryprograms.We expectincreasedexpensesaswecontinueourresearchanddevelopment,initiateadditionalclinicaltrials,and seekmarketingapprovalforourleadprogramsandourotherproductcandidates.In addition,ifwe obtain marketingapprovalforany of our productcandidates,we expectto incursignificantcommercializationexpenses relatedtoproductmanufacturing,marketing,salesanddistribution.Furthermore,we expectto continueto incur additionalcostsassociatedwithoperatingas a publiccompany.Accordingly,we willneed to obtainsubstantial additionalfundinginconnectionwithourcontinuingoperations.Adequateadditionalfinancingmaynot be availabletous on favorableterms,or atall.In addition,we mayseekadditionalcapitaldue to favorablemarket conditionsorstrategicconsiderationsevenifwebelievewehavesufficientfundsforourcurrentor

future operatingplans.Ifweareunabletoraisecapitalwhenneededoronfavorableterms,we couldbe forcedto delay, reduceor eliminateour researchand developmentprograms,our commercializationplansor otheroperations.

Webelievethatourexistingcash, cashequivalents, and marketable securities will enable us to fund our operating expenses, and capital expenditure requirements into the second half of 2024. We have based this estimate on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect. Changes beyond our control may occur that would cause us to use our available capital before that time, including changes in and progress of our drug development activities and changes in regulation. Our future capital requirements will depend on many factors, including:

We willrequireadditionalcapitalto completeour planned clinical developmentprogramsforourcurrentproductcandidatesto obtainregulatoryapproval.Our abilityto raise additionalfundswilldepend on financial,economicand marketconditionsand otherfactors,overwhich we may havenoorlimitedcontrol.Ifadequatefundsarenotavailableoncommerciallyacceptabletermswhenneeded, wemaybeforcedtodelay,reduceorterminatethedevelopmentorcommercializationofallorpartofour researchprogramsorproductcandidatesor we maybe unableto takeadvantageof futurebusinessopportunities. Furthermore,any additionalcapital-raisingeffortsmaydivertour managementfrom their day-to-dayactivities, whichmayadverselyaffectourabilitytodevelopandcommercializeourcurrentandfutureproductcandidates, ifapproved.

Raising additionalcapitalmaycause dilutionto our stockholders,restrictour operationsor requireus to relinquishrightsto our technologiesor product candidates.

Untilsuchtime,ifever,aswe can generatesubstantialproductrevenue,we expectto financeour cashneeds throughacombinationofequityofferings,debtfinancings,collaborations,strategicalliancesand marketing, distributionorlicensing

arrangements.Inaddition,wemayseekadditionalcapitaldue to favorablemarket conditionsorstrategicconsiderations,evenifwebelievewehavesufficientfundsforour currentor future operatingplans.Totheextentthatweraiseadditionalcapitalthroughthesaleof equityor convertibledebt securities,yourownershipinterestwillbe diluted,and thetermsof thesesecuritiesmayincludeliquidationor otherpreferencesthatadverselyaffectyourrightsasacommonstockholder.Debt financingand preferredequity financing,ifavailable,mayinvolveagreementsthatincludecovenantslimitingor restrictingour abilityto take specificactions,suchasincurringadditionaldebt,makingacquisitionsor capitalexpendituresor declaring dividends.

Ifwe raiseadditionalfundsthroughcollaborations,strategicalliancesor marketing,distributionor licensing arrangementswiththirdparties,wemayhavetorelinquishvaluablerightstoourtechnologies,futurerevenue streams,researchprogramsorproductcandidatesorgrantlicensesontermsthatmaynotbefavorabletous.If weareunabletoraiseadditionalfundsthroughequityordebtfinancingsor otherarrangementswhen needed,we may be required to delay, limit, reduce or terminate our research, product development or future commercializationeffortsorgrantrightstothirdpartiestodevelopandmarketproductcandidatesthatwewould otherwisepreferto developand marketourselves.

Risks Relatedto Design and Developmentof our Product Candidates

We are highlydependenton the successof our productcandidates,PRT543,PRT811,PRT1419 and PRT2527, which are in earlyclinicaldevelopment. We have not completedsuccessfullate-stagepivotalclinicaltrialsor obtainedregulatoryapprovalforany product candidate.We mayneverobtainapprovalforany of our productcandidatesor achieveor sustain profitability.

Our futuresuccessishighlydependenton our abilityto obtainregulatoryapprovalfor,and thensuccessfully commercialize,ourproductcandidates,PRT543,PRT811, PRT1419 and PRT2527. Weareearlyinourdevelopmentefforts andourleadproductcandidates,PRT543,PRT811, PRT1419 and PRT2527,areeachcurrentlyinaPhase1clinicaltrial. Ourotherproductcandidates areinearlierstagesofdevelopment.Wecurrentlyhaveno productsthatareapprovedforsaleinanyjurisdiction.TherecanbenoassurancethatPRT543, PRT811, PRT1419, PRT2527 or our otherproductcandidatesin developmentwillachievesuccessin theirclinicaltrialsor obtainregulatoryapproval.

Ourabilitytogenerateproductrevenues,which we do not expectwilloccurformanyyears,ifever,will dependheavilyonthesuccessfuldevelopmentandeventualcommercializationofPRT543, PRT811, PRT1419, PRT2527 orotherproductcandidatesindevelopment.The successof our productcandidates,includingPRT543, PRT811,PRT1419and PRT2527,willdepend on severalfactors,includingthefollowing:

• successful completion of preclinical studies and clinical trials;

• developing and implementing marketing and reimbursement strategies;

• effectively competing with other therapies;

Manyofthesefactorsarebeyondourcontrol,anditispossiblethatnone of our productcandidateswillever obtainregulatoryapprovalevenifweexpendsubstantialtimeandresourcesseekingsuchapproval.Ifwedo not achieveoneormoreofthesefactorsinatimelymanneroratall,we couldexperiencesignificantdelaysor an inabilityto successfullycommercializeour productcandidates,which would materiallyharmour business. For example,ourbusinesscouldbeharmedifresultsofourongoingclinicaltrialsofPRT543, PRT811, PRT1419 or PRT2527, varyadverselyfromour expectations.

Drug developmentinvolvesa lengthyand expensiveprocess,and clinicaltestingisuncertainas to the outcome.

We currentlyhave threeproductcandidatesin Phase 1 clinicaldevelopmentand additionalproduct candidatesinpreclinicaldevelopment,andtheriskof failureforeachishigh. We areunableto predictwhen or if ourproductcandidateswillproveeffectiveorsafeinhumansor willobtainmarketingapproval.Beforeobtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinicaldevelopmentand thenconductextensiveclinicaltrialsto demonstratethesafetyand efficacyof our productcandidatesinhumans.Clinicaltestingisexpensive,difficulttodesignandimplement,cantakemany yearsto completeand isuncertainas to theoutcome.

Afailureofoneormoreclinicaltrialscanoccuratanystageof testing.The outcomeof preclinicaltesting andearlyclinicaltrialsmaynotbepredictiveofthesuccessof laterclinicaltrialsor of clinicaltrialsof thesame productcandidatesinotherindications,andinterimorpreliminaryresultsofaclinicaltrialdonotnecessarily predictfinalresults.Later-stageclinicaltrialscoulddifferin significantways fromearly-stageclinicaltrials, includingchangestoinclusionandexclusioncriteria,efficacyendpoints,dosingregimenandstatisticaldesign. Inparticular,thesmallnumberofpatientsinourcurrentPhase1clinicaltrialsmaymaketheresultsofthese trialslesspredictiveoftheoutcomeoflaterclinicaltrials.In addition,althoughwe have observedencouraging clinicalactivityinthedoseescalationportionofthePhase1portionofourongoingPRT543 andPRT811 clinical trials,theprimaryobjectivesweretodeterminethesafety,tolerabilityand maximumtolerateddose of PRT543 andPRT811,respectively,andtodeterminearecommendedPhase2dosefortheexpansionportionofour Phase1clinicaltrials,andnottodemonstrateefficacy.Theassessmentsofclinicalactivityfromthisportionof theclinicaltrials,someofwhichwerenotpre-specified,maynotbepredictiveoftheresultsin dose expansion cohorts,specifictumortypesorfurtherclinicaltrialsofPRT543 andPRT811. Inaddition,whilewemaybelieve certainresultsin patients,such as stabledisease,suggestencouragingclinicalactivity,stabledisease is not consideredaresponseforregulatorypurposes.Stabledisease,orSD,isdefinedasfailuretomeetthedefinition ofobjectiveclinicalresponseor progressivedisease.Furthermore,safetyeventsmaybe observedin latertrials thataltertheanticipatedrisk-benefitprofilesof PRT543and PRT811.

We mayincur additionalcostsor experiencedelaysin completing,or ultimatelybe unable to completethe developmentand/or commercializationof PRT543,PRT811,PRT1419,PRT2527or our otherproduct candidates.

Beforewecaninitiateclinicaltrialsofaproductcandidateinanyindication,we mustsubmittheresultsof preclinicalstudiestotheFDA ortocomparableforeignauthorities,respectively,alongwithotherinformation, includinginformationabouttheproductcandidate’schemistry,manufacturingand controlsand our proposed clinicaltrialprotocol,as partof an IND or comparableforeignregulatoryfilings.

TheFDA mayrequireustoconductadditionalpreclinicalstudiesforany productcandidatebeforeitallows ustoinitiatesubsequentclinicaltrialsunderanyIND,whichmayleadto additionaldelaysand increasethecosts of our preclinicaldevelopmentprograms.

Anydelaysinthecommencementorcompletionof our ongoing, plannedor futureclinicaltrialscould significantlyaffectour productdevelopmentcosts.We mayexperiencenumerousunforeseeneventsduring,or as aresultof,clinicaltrialsthatcoulddelayorpreventourabilitytoobtainmarketingapprovalorcommercialize our productcandidates,including:

• lack of adequate funding to continue the clinical trial;

• changes to clinical trial protocol;

Delays,includingdelayscausedbytheabove factors,can be costlyand couldnegativelyaffectour abilityto completeaclinicaltrialorobtaintimelymarketingapprovals.Wedonotknowwhetheranyofourplanned preclinicalstudiesorclinicaltrialswillbeginon a timelybasisor atall,willneed to be restructuredor willbe completedonschedule,oratall.Forexample,theFDA mayplaceapartialorfullclinicalholdonanyofour clinical trials for a variety of reasons, including safety concerns and noncompliance with regulatory requirements.Ifwearenotabletocompletesuccessfulclinicaltrials,wewillnotbeableto obtainregulatory approvaland willnot be ableto commercializeour productcandidates.

Significantpreclinicalorclinicaltrialdelaysalsocouldshortenany periodsduringwhich we mayhave the exclusiverighttocommercializeourproductcandidatesorallowourcompetitorstobringproductstomarket beforewedoandimpairourabilitytosuccessfullycommercializeourproductcandidatesand mayharmour businessand resultsof operations.

Ifwe experiencedelaysor difficultiesin enrollingpatientsin our ongoing or planned clinicaltrials,our receiptof necessaryregulatoryapprovalcould be delayedor prevented.

Wemaynotbeabletoinitiateorcontinueourongoingorplannedclinicaltrialsforourproductcandidates ifweareunabletoidentifyandenrollasufficientnumberofeligiblepatientsto participatein thesetrialsas requiredbytheFDA orcomparableforeignregulatoryauthorities.In addition,someof our competitorscurrently haveongoingclinicaltrialsforproductcandidatesthatwouldtreatthesamepatientsas our clinicalproduct candidates,andpatientswhowouldotherwisebe eligibleforour clinicaltrialsmayinsteadenrollin clinicaltrials ofourcompetitors’productcandidates.ThisisacutelyrelevantforourdevelopmentofPRT543 forthetreatment ofpatientswithmyeloidmalignanciesandothersolidtumors,includingadenoidcysticcarcinoma,or ACC, indicationsforwhichinvestigationaldrugsbyourcompetitorsarecompetingforclinicaltrialparticipants. Patientenrollmentisalsoaffectedby otherfactors,including:

• severity of the disease under investigation;

• the incidence and prevalence of our target indications;

• competing studies or trials with similar eligibility criteria;

• eligibility criteria defined in the protocol for the trial in question;

• efforts to facilitate timely enrollment in clinical trials;

• the ability to monitor patients adequately during and after treatment;

• our ability to obtain and maintain patient consents; and

• proximity and availability of clinical trial sites for prospective patients.

Ourinabilitytoenrolland maintaina sufficientnumberof patientsforour clinicaltrialswould resultin significantdelaysormayrequireustoabandononeormoreclinicaltrialsaltogether.Enrollmentdelaysin our clinicaltrials,includingduetotheCOVID-19pandemic,mayresultinincreaseddevelopmentcosts,which would causethevalueof our companyto declineand limitour abilityto obtainadditionalfinancing.

The COVID-19pandemiccould adverselyimpactour business,includingour clinicaltrialsand clinical trialoperations.

TheCOVID-19 pandemicintheUnitedStatesand in othercountriesin which we have plannedor have activeclinicaltrialsitesand where our third-partymanufacturersoperate, could cause significantdisruptionsthat couldseverelyimpactour businessand clinicaltrials,including:

• inability or unwillingness of subjects to travel to the clinical trial sites;

Suchdisruptionscouldimpede,delay,limitorpreventcompletionofour ongoing clinicaltrialsand preclinicalstudiesor commencementof new clinicaltrialsand ultimatelyleadto thedelayor denialof regulatory approvalofourproductcandidates,whichwouldseriouslyharmour operationsand financialconditionand increaseourcostsandexpenses.WeareinclosecontactwithourCROs, CMOsandclinicalsitesasweseekto mitigatetheimpactof theCOVID-19 pandemic onourstudiesand currenttimelines.Measureswe have takenin responseto the COVID-19 pandemic include,where feasible,conductingremoteclinicaltrialsiteactivationsand datamonitoring,and limitingon-sitepatientvisitsby adjustingpatientassessmentsand protocol.However, despitetheseefforts,we haveexperiencedlimiteddelaysin trialsiteinitiations,patientparticipationand patientenrollmentin someof our clinicaltrialsandwemaycontinueto experiencesomedelaysin our clinicaltrialsand preclinicalstudiesand delaysin datacollectionand analysis.These delaysso farhave had a limitedimpact,but thismaychangeas the COVID-19 pandemicandtheresponsetosuchCOVID-19 pandemiccontinuestoevolve,and couldhave an adverseimpactonourtimelinesandourbusiness.TheCOVID-19 pandemiccouldalsoaffectthebusinessofthe FDA, EMAorotherhealthauthorities,whichcouldresultin delaysin meetingsrelatedto plannedor completed clinical trials and ultimately of reviews and approvals of our product candidates. The global COVID-19 pandemiccontinuestorapidlyevolve.TheextenttowhichtheCOVID-19pandemicmayimpactourbusiness andclinicaltrialswilldependonfuturedevelopments,which arehighlyuncertainand cannotbe predictedwith confidence, such as the ultimate geographic spread of the disease, the duration of the pandemic, travel restrictions and social distancing in the United States and other countries, business closures or business disruptionsandtheeffectivenessofactionstakenintheUnitedStatesand othercountriesto containand treatthe disease.

Adversesideeffectsor othersafetyrisksassociatedwith PRT543,PRT811,PRT1419, PRT2527or our otherproduct candidatescould delayor precludeapproval,cause us to suspend or discontinueclinicaltrialsor abandon furtherdevelopment,limitthe commercialprofileof an approvedproduct,or resultin significantnegativeconsequencesfollowingmarketingapproval,ifany.

PRLD US Equity

PRLD · 10-K · period ended 2021-12-31

Item 1. Business.

Item 1A. Risk Factors

PRLD US Equity☆

PRLD · 10-K · period ended 2021-12-31

Item 1. Business.

Item 1A. Risk Factors

PRLD US Equity